Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reduced expression of the metastasis suppressor gene nm23-H1 has been previously correlated with high tumor metastatic potential and fatal clinical outcome in several types of human carcinomas. The aim of the study was to identify the expression of nm23-H1 in a variety of premalignant and malignant cervical lesions. The study comprised 106 cervical biopsies obtained from 106 women ranging in age from 23 to 68 (median 42) years. Histologic slides stained with H&E were evaluated blindly by two pathologists and a consensus diagnosis was established for each case. In addition, immunohistochemical stain was employed and a monoclonal antibody against nm23-H1 (YLEM Rome, Italy) was used. Twenty-five of the cervical biopsies showed changes of mild dysplasia (CIN I), whereas 28 demonstrated features of moderate dysplasia (CIN II) and 28 severe dysplasia (CIN III). In 25 cases infiltrating squamous cell carcinoma was identified. Expression of nm23-H1 was evident in 9/25 (36%) CIN I, 13/28 (46%) CIN II, 22/28 (78.5%) CIN III and 17/25 (68%) infiltrating carcinoma biopsies. Statistically significant differences were observed between CIN II and CIN III (p=0.003), and CIN II and infiltrating carcinoma (p=0.002) groups. Expression of the nm23-H1 gene in premalignant and malignant cervical lesions indicates that this gene may play a substantial role in carcinogenesis and tumor progression.
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PMID:Immunohistochemical analysis of nm23-H1 expression in human cervical lesions. 1119 46

Human papillomavirus type 16 is a major factor in cervical carcinogenesis. Inappropriate cytokine synthesis may direct the local immune response away from a type-1 (cellular) pattern and may subsequently contribute to the development and progression of precancer. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) using a competitive mimic was carried out to determine type-1 (interferon gamma (IFN-gamma)) and type-2 (interleukin-10 (IL-10)) cytokine mRNA levels in whole cervical specimens (without microdissection) from seven normal and nine HPV-16 positive CIN formalin-fixed paraffin-embedded tissues. Microdissection was used to measure separately the epithelial and sub-epithelial levels of IFN-gamma and IL-10 mRNAs in 11 specimens of normal cervix and 25 HPV-16 positive CIN (nine CIN 1, seven CIN 2 and nine CIN 3). IFN-gamma mRNA was lower in CIN than normal (p=0.04). IL-10 mRNA level in CIN was significantly higher (p=0.005) than in normal cervix (before microdissection). Epithelial IFN-gamma mRNA showed a significant decrease in all grades of CIN (median=3.58) compared with normal (7.74) (p<0.05), but there was no significant difference between the grades. A significant decrease in sub-epithelial IFN-gamma mRNA was found in CIN 1(9.81), CIN 2 (3.82) and CIN 3 (4.62) compared with normal cervix (27.35) (p<0.05). Also, sub-epithelial IFN-gamma mRNA was significantly lower in CIN 2 and CIN 3 than in CIN 1 (p=0.005 and 0.0005, respectively). IL-10 was detected in the epithelium of only one of 11 normal and one of 25 CIN, but sub-epithelial IL-10 was significantly higher in CIN 2 (0.08) and CIN 3 (0.26) than in normal (0.00) (p=0.036 and 0.0032, respectively). There was no significant difference in the sub-epithelial level of IL-10 between normal and CIN 1 (0.00) (p=0.96). Our results suggest that reduced epithelial and sub-epithelial IFN-gamma, as well as increased sub-epithelial IL-10 synthesis may play a role in the development and progression of HPV-16 associated cervical precancer.
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PMID:Quantitative analysis of IL-10 and IFN-gamma mRNA levels in normal cervix and human papillomavirus type 16 associated cervical precancer. 1159 96

To identify cellular genes that may be involved in human papillomavirus (HPV)-mediated immortalization mRNA differential display analysis was performed on preimmortal and subsequent immortal stages of four human keratinocyte cell lines transformed by HPV type 16 or 18 DNA. This yielded a cDNA fragment encoding the transcription factor GATA-3 that was strongly reduced in intensity in all immortal stages of the four cell lines. A marked reduction in both GATA-3 mRNA and protein expression in HPV-immortalized cell lines was confirmed by reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemistry and was also shown to be apparent in cervical carcinoma cell lines. Immunohistochemical analysis of cervical tissue specimens showed a clear nuclear staining for GATA-3 in normal cervical squamous epithelium (n = 14) and all cervical intraepithelial neoplasia (CIN) I (n = 6) and CIN II lesions (n = 2). In contrast, 11% (1 of 9) of CIN III lesions and 67% (8 of 12) of cervical squamous cell carcinomas revealed a complete absence of GATA-3 immunostaining. Hence, complete down-regulation of GATA-3 expression represents a rather late event during cervical carcinogenesis. Whether GATA-3 down-regulation is etiologically involved in HPV-mediated immortalization and cervical carcinogenesis remains to be examined.
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PMID:Down-regulation of GATA-3 expression during human papillomavirus-mediated immortalization and cervical carcinogenesis. 1205 98

This report describes the appearance of ectopic chromosome around centrosome (ECAC) in metaphase cell nuclei of high-risk HPV-associated cervical neoplasms. ECAC are clearly visible on HE-stained sections as a tiny (approx. 0.7 micro), round, dark structure or an aggregate of filamentous chromosome, often symmetrical at bilateral centrosomes. They appear in CINs from an early stage (CIN I), with the highest incidence in HPV16-associated CIN II-III (75%), and are less common in HPV-related invasive carcinomas (21%) and in lesions associated with high-risk HPV types other than 16. Rates for ECAC-positive nuclei in metaphase preparations (ECAC rate) for each lesion ranged 3.6-30%, the average being 14.5%. ECAC appeared very rarely in CINs associated with intermediate-risk HPVs and was never encountered in HPV6/11-induced condylomas or HPV-unrelated neoplasms in other organs. ECAC may be morphologic evidence of HPV-induced chromosomal instability working as a background mechanism in cervical carcinogenesis and also a useful marker for the histopathologic differentiation of high-risk CINs.
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PMID:Ectopic chromosome around centrosome in metaphase cells as a marker of high-risk human papillomavirus-associated cervical intraepithelial neoplasias. 1280 Jan 90

Cervical carcinogenesis has well-defined stages of disease progression including three grades of pre-invasive lesions--cervical intraepithelial neoplasia grades 1-3 (CIN 1-3)--and invasive cervical cancer. However, the biological properties of CIN lesions prone to develop invasive disease are not well defined. Recent observations suggest that early invasive disease spreads to regional lymph nodes in several tumour types and that growth factors (VEGF-C and VEGF-D) involved in new lymphatic vessel formation may play a crucial role in this process. The present study has assessed the expression of VEGF-C and VEGF-D, and their receptor VEGFR-3, in 152 cervical lesions (33 CIN 1, 33 CIN 2, 37 CIN 3, and 49 squamous cell carcinomas) to determine whether expression of lymphangiogenic factors occurs prior to invasion. The presence of lymphatic vessels was determined using LYVE-1 and podoplanin staining, as well as double immunostaining for LYVE-1/CD34 and podoplanin/CD34. In situ hybridization was performed to determine VEGFR-3 mRNA expression. A significant positive correlation was found between VEGF-C, VEGF-D, and VEGFR-3 expression through the different stages of cervical carcinogenesis. Significant differences in protein expression for VEGF-C, VEGF-D, and VEGFR-3 were found between CIN 1-2 and CIN 3 (p<0.001 for all), but not between CIN 3 and cervical cancer. More than 50% of the CIN 3 lesions showed moderate to strong staining for VEGF-C and VEGF-D, whereas most of the early pre-cancerous lesions (CIN 1 and 2) were negative. In cervical cancer, similar observations to those in CIN 3 were found. VEGFR-3 mRNA expression was found in the cytoplasm of epithelial neoplastic cells and VEGFR3 protein expression was found in more than 50% of CIN 3 lesions and cervical cancers, compared with 15% in CIN 1 and 2. These findings suggest an autocrine growth stimulation pattern via VEGFR-3. Adjacent CIN 3 was present in nine cervical cancers and displayed strong expression for VEGF-C, VEGF-D, and VEGFR-3. These results suggest that in cervical carcinogenesis a switch to the lymphangiogenic phenotype may occur at the stage of CIN 3.
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PMID:Expression of vascular endothelial growth factor (VEGF)-C and VEGF-D, and their receptor VEGFR-3, during different stages of cervical carcinogenesis. 1464 57

The high-risk human papillomavirus is known to play a pivotal role in cervical carcinogenesis. Numerical and structural aberrations are known to be related to different behaviors of malignant cervical lesions. The aims of this study were (1) to assess the number of cervical cells with chromosome 1 aneusomy (monosomy, trisomy, and tetrasomy) in 20 women with cervical intraepithelial neoplasia (CIN 1, CIN 2, CIN 3, and invasive cancer) and three women without CIN by fluorescence in situ hybridization (FISH), (2) to determine the heterogeneity of aneusomy among women within each of the five groups studied, (3) to determine the association between the four progressive stages of cervical cancer and the number of cells with and without aneusomy, (4) to determine the association between number of cells with and without aneusomy and human papilloma virus (HPV) infection, and (5) to determine its usefulness as a biomarker of cancer risk. A hospital-based unmatched case-control study in a sample of 23 women grouped by disease stage and selected by histology from the Obstetrics and Gynecology Hospital of the Instituto Mexicano del Seguro Social (IMSS) in Mexico was conducted in 2002. Numerical aberrations of chromosome 1 in cervical smears were detected with FISH. HPV was detected with polymerase chain reaction (PCR) and typing was performed with restriction fragment length polymorphism (RFLPs). Analysis of chromosome 1 aneusomy revealed (1) homogeneity among women within each one of the five groups, (2) a positive linear trend between the aneusomy frequency and grade of lesion, and (3) an association between aneusomy and high-risk HPV infection. These findings suggest the usefulness of the number of cervical cells with chromosome 1 aneusomy as a biomarker. In order to validate this biomarker we suggest a larger prospective study of cytological samples of patients with a longer follow-up.
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PMID:Association between the stages of cervical cancer and chromosome 1 aneusomy. 1586 Mar 56

Methylation of p16 is an important mechanism in cervical carcinogenesis. However, the relationship between cervical squamous cell carcinoma (SCC) and Epstein-Barr virus (EBV) remains controversial. Here, we explored whether EBV infection and/or p16 gene inactivation would play any role in cervical carcinogenesis. Eighty-two specimens included 41 invasive SCCs, 30 cervical intraepithelial neoplasm (CIN; CIN 1, 11 cases, CIN II, 3 cases, CIN III 16 cases) and 11 nonneoplastic cervices. EBV was detected by polymerase chain reaction (PCR) for EBNA-1 and in situ hybridization for EBER-1. The p16 methylation-status and the expression of p16 protein were studied by methylation-specific PCR and immunohistochemistry, respectively. The materials were divided into four groups: 1) nonneoplastic cervices, 2) CIN I, 3) CIN II-III and 4) invasive SCCs. p16 methylation and p16 immunoexpressions increased in CIN and invasive SCCs than nonneoplastic tissue. p16-methylation and p16-immunoreactivities were higher in the EBV-positive group (p=0.009, p<0.001) than in the EBV-negative group. EBV was detected more frequently in CIN and SCCs than nonneoplastic cervices. In conclusion, a correlation between p16 methylation, p16 immunoreactivity and the detection of EBV strongly suggested that the cooperation of EBV and p16 gene may play a synergic effect on cell cycle deregulation.
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PMID:Epstein-Barr virus and p16INK4A methylation in squamous cell carcinoma and precancerous lesions of the cervix uteri. 1610 Apr 57

The hedgehog (Hh)-signaling pathway plays an essential role in normal development. Deregulation of this pathway is responsible for several types of cancers. The aim of this study was to determine the expression pattern and the extent of Hh-signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions. A total of 106 uterine cervical cancers and related lesions (37 squamous cell carcinomas, 23 cervical intraepithelial neoplasia (CIN) III, 10 CIN II, four CIN I, 32 normal cervical epithelia) were immunohistochemically analyzed with anti-Shh, Indian Hh (Ihh), Patched (PTCH), Smoothened (Smo), Gli-1, Gli-2, Gli-3 antibodies on paraffin blocks. The results showed that the expression of all the Hh-signaling molecules was greatly enhanced in uterine cervical tumors, including carcinoma and its precursor lesions. The staining pattern was mainly cytoplasmic except for Gli-1/2, whose expression was observed in both cytoplasm and nucleus. In case of Ihh, PTCH, Smo and Gli-1, their expression in normal epithelium was completely absent or rare. The expression of all the seven Hh-signaling molecules mentioned above was significantly increased in CIN II/III and carcinoma, compared with that in normal epithelium (P < 0.05). The expression of Shh was increased by double; the first increase occurred in normal epithelium-CIN transition, and the second, during the progression of CIN to carcinoma. These results strongly suggest that the Hh-signaling pathways were extensively activated in carcinoma and CIN of uterine cervix. In conclusion, the Hh-signaling pathways may be involved in carcinogenesis of squamous cell carcinoma of uterine cervix and can be considered as a potential therapeutic target.
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PMID:Enhanced expression of hedgehog signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions. 1677 29

Recently proposed events associated with the progression of cervical intraepithelial neoplasia (CIN) 2/3 to cervical carcinoma include integration of human papillomavirus (HPV) into the host genome, genomic instability, and an increase in chromosome 3q copy number. In particular, the gene coding for the RNA component of telomerase (TERC) at 3q26 has been implicated as a possible candidate gene. Since it is not known to date how these events are temporally related during cervical carcinogenesis, the aim of the present study was to assess the correlation between TERC gene copy number and the physical status of HPV during progression in cervical neoplasia. Solitary precursor lesions of the uterine cervix (CIN 2/3, n = 17), lesions associated with a micro-invasive carcinoma (CIN 3&mCA, n = 13), and advanced invasive carcinomas (invCA, n = 7) were analysed by fluorescence in situ hybridization (FISH) to determine the physical status of the virus and TERC gene copy number. The TERC gene was increasingly gained with progression of CIN 2/3 (3 of 17) through CIN 3&mCA (7 of 13) to invCA (5 of 7). In the lesions exhibiting gain of TERC, the virus was predominantly integrated. This was seen in eight of ten diploid lesions, indicating that these events can occur prior to aneuploidization and are strongly associated with the progression of CIN 3 to mCA and invCA (p < 0.001). With progression to carcinoma, a number of these lesions show polyploidization, resulting in aneuploidy and high TERC gene copy numbers. In conclusion, genomic integration of oncogenic HPV and gain of the human telomerase gene TERC appear to be important associated genetic events in the progression of uterine cervical dysplasia to invasive cancer.
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PMID:Genomic integration of oncogenic HPV and gain of the human telomerase gene TERC at 3q26 are strongly associated events in the progression of uterine cervical dysplasia to invasive cancer. 1705 8

Signal transducer and activator of transcription 3 (STAT3) has been regarded as an oncogene in many types of cancers. However, its role in cervical carcinogenesis is not well determined. The purpose of this study was to evaluate the expression patterns of STAT3 in cervical intraepithelial neoplasia (CIN), normal cervix (NC), and squamous cell carcinoma (SCC) to explore its possible role in cervical carcinogenesis. Paraffin-embedded sections from 83 patients including 20 CIN 1, 10 CIN 2, 26 CIN 3, and 27 comparative cases of 10 NC and 17 stage Ib SCC were collected in this study. Immunohistochemistry was performed to analyze the expression patterns of STAT3, and the results obtained were categorized by a semiquantitative method and were further correlated with the CIN histopathologic grade and the proliferation marker, Ki-67, using the chi2 test. Our results showed that nuclear STAT3 expression was predominantly in the squamous epithelial cells, and that high-grade CIN and stage Ib SCC lesions had a higher nuclear STAT3 expression when compared with NC and CIN 1. Furthermore, the nuclear STAT3 expression in CIN was significantly correlated with Ki-67 expression (p = 0.025), but not CIN lesion grade. In summary, our results indicate that an altered STAT3 expression in CIN is correlated with cell proliferation but may not have a direct contribution to cervical carcinogenesis.
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PMID:Positive association between STAT3 and Ki-67 in cervical intraepithelial neoplasia. 1711 Mar 42


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