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RESUMEN Introducción: El Virus de Papiloma Humano se considera un factor clave en el desarrollo de lesiones cérvico uterinas. No obstante, la infección per se no es suficiente para desarrollar todos los eventos carcinogénicos, de manera que estos podrían estar regulados por vías de señalización celular. Las señales transmitidas hacia el interior de la célula, se producen a través de cascadas de señalización, en las que intervienen numerosas proteínas que ganan y/o pierden su actividad biológica, regulando así el metabolismo, la transcripción y traducción de genes. Objetivo: Proveer información actualizada sobre las vías de señalización TLRs, Wnt/ß-catenina y PI3K/Akt implicadas en la carcinogénesis cervical. Métodos: Se realizó una revisión de la literatura especializada mediante artículos originales y revisiones publicadas en bases de datos pertenecientes a los sitios web PubMed, Google Scholar, EBSCO y NCBI, en idiomas español e inglés. Resultados: Se constató que la vía TLR juega un rol clave en el combate a virus, bacterias y otras infecciones, además de poseer actividad inmune antitumoral. La vía Wnt/ß-catenina participa en varios procesos biológicos como la diferenciación, migración y adhesión celular, mientras que, PI3K/Akt está relacionada con el crecimiento, la motilidad y la supervivencia celular. Conclusiones: La activación o desregulación de algunos componentes de estas vías están implicadas en la proliferación incontrolada de células tumorales, evento importante en la carcinogénesis cervical(AU)
ABSTRACT Introduction: Human papillomavirus is considered a key factor in the development of uterine cervical lesions. However, infection per se is not enough to develop all carcinogenic events, so that these could be regulated by cell signaling pathways. The signals transmitted into the cell are produced through signaling cascades, which involve numerous proteins that gain and, or lose their biological activity, thus regulating the metabolism, transcription and translation of genes. Objective: To provide updated information on TLRs, Wnt / ß-catenin and PI3K / Akt signaling pathways involved in cervical carcinogenesis. Methods: A review of specialized literature was carried out through original articles and reviews published in PubMed, Google Scholar, EBSCO databases and NCBI websites, in Spanish and English languages. Results: TLR pathway was found to play a key role in the fight against viruses, bacteria and other infections, as well as having antitumor immune activity. The Wnt / ß-catenin pathway participates in several biological processes such as cell differentiation, migration and adhesion, while PI3K / Akt is related to cell growth, motility and survival. Conclusions: The activation or deregulation of some components of these pathways are involved in uncontrolled proliferation of tumor cells, an important event in cervical carcinogenesis(AU)
Subject(s)
Humans , Female , Uterine Cervical Neoplasms/diagnosis , Papillomavirus Infections/etiology , Carcinogenesis/pathology , Review Literature as Topic , Databases, BibliographicABSTRACT
Objective@#To explore the effects of hnRNP E1 and both early genes E2 and E6 of HPV16 as well as their interactions in the progression of cervical carcinogenesis.@*Methods@#Subjects of this study included 56 women with normal cervix (NC), 58 patients with low-grade cervical intraepithelial neoplasm (CINⅠ) and 50 patients with high-grade cervical intraepithelial neoplasm (CINⅡ/Ⅲ) who were all recruited from the 'Cervical Lesions Study Cohort Project’ in Jiexiu of Shanxi province from June to September, 2014. Another 40 patients with cervical squamous cell carcinoma (SCC) were from the Shanxi Tumor Hospital during the same period. Information related to cervical lesions were collected, using a structured questionnaire, with cervical tissues and cervical exfoliated cells gathered from all the participants. HPV infection was detected by flow-through hybridization, while the levels of expression on hnRNP E1, HPV16 E2 and E6 protein were measured by Western Blot. Kruskal-Wallis H test, χ2 test, trend χ2 test were analyzed by SPSS 22.0 software, while interaction was evaluated by generalized multifactor dimensionality reduction (GMDR).@*Results@#The overall infection rates of HPV16 related to CINⅠ (15.52%, 9/58), CINⅡ/Ⅲ (40.00%, 20/50) and SCC (67.50%, 27/40) groups were all higher than that of the NC group (8.93%, 5/56) and with an increasing trend on the severity of cervical lesions (trend χ2=43.613, P<0.001). The levels of expression on hnRNP E1 protein were significantly different in the groups with different cervical lesions (H=9.98, P=0.019), showing a decreasing trend with the severity of cervical lesions (trend χ2=9.495, P=0.002). The levels of expression on HPV16 E2 (H=16.20, P=0.001) and HPV16 E6 (H=15.44, P=0.001) were significantly different in groups with different cervical lesions. Results of GMDR showed that the best interaction model in both groups of CINⅡ/Ⅲ and SCC appeared as hnRNP E1 low expression, HPV16 E2 low expression and HPV16 E6 high expression. However, no similar interaction was seen in CINⅠ (P>0.05).@*Conclusions@#Both low expressions of hnRNP E1 and abnormal expression of HPV16 E2 and E6 could increase the risk of high-grade CIN and cervical cancer. It seemed that they might have an important synergistic effect on the progression of cervical cancer.
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Objective To explore the relationship between abnormal expression of fragile histidine triad (FHIT) gene and methyl-CpG-binding protein 2 (MeCP2) as well as their interaction on cervical cancerization.Methods A total of 73 patients with cervical squamous cell carcinoma (SCC),113 patients with cervical intraepithelial neoplasia (CIN Ⅰ,n =45;CIN Ⅱ/Ⅲ,n=68) and 60 women with normal cervix (NC) were included in the study.Real time PCR and Western blot were performed to detect the expression levels of mRNA and protein about FHIT and MeCP2,respectively.The methylation status of FHIT gene CpG island was tested by methylation-specifc PCR (MSP).Kruskal-Wallis H test,x2 test,trend x2 test and Spearman correlation analysis were conducted with software SPSS 20.0.The interaction was evaluated by generalized multifactor dimensionality reduction (GMDR) model.Results With the deterioration of cervical lesion,the methylation rates of FHIT gene CpG island (x2=18.64,P＜0.001;trendx2=18.08,P＜0.001) increased gradually,while the expression levels of FHIT mRNA (H=27.32,P＜0.001;trendx2=12.65,P＜0.001) and protein (H=47.10,P＜0.001;trendx2=29.79,P＜0.001) decreased gradually.There was a negative correlation between the methylation rates of FHIT gene CpG island and the expression level of FHIT protein (r=-0.226,P＜0.001).The levels of MeCP2 mRNA (H=26.19,P＜0.001;trend x2=11.81,P=0.001) and protein (H=69.02,P＜ 0.001;trend x2 =47.44,P＜ 0.001) increased gradually with the aggravation of cervical lesions.There was a positive correlation between the expression level of MeCP2 protein and the FHIT mRNA Ct ratio (r=0.254,P＜0.001).Expression of proteins were negatively correlated between MeCP2 and FHIT (r=-0.213,P=0.001).The results analyzed by GMDR model showed that there were interactions among high MeCP2 protein expression,the CpG island methylation of FHIT and mRNA and protein expression in CIN Ⅱ/Ⅲ group,and among high MeCP2 mRNA and protein expression,the CpG island methylation of FHIT and low mRNA and protein expression in SCC group.Conclusion High expression of MeCP2 mRNA and protein,the CpG island methylation and low mRNA and protein expression of FHIT could increase the risk of cervical carcinogenesis,and there might be a synergistic effect on cervical carcinogenesis.
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Objective The aims of this study were to compare the different expression between high-risk human papilloma-virus load(HR-HPV DNA)and Th1/Th2 type cytokines in local different microenvironments of cervix,and to explore the possibility and significance of predicting cervical cancer. Methods A total of 339 patients with persistent HR-HPV infection were divided into cervical intraepithelial neoplasia(CIN)and cervical cancer. Forty patients with HPV-negative and cytological examination of normal cervix were used as controls. PCR fluorescence assay and double antibody sandwich were used. ELISA assay were used to detect HPV-DNA and Th1 type cytokines including IL-2,IFN-γ,TNF-ɑ and Th2 type cytokines including IL-4,IL-6 and IL-10 from cervical secretion. The ratio of TNF-ɑ/IL-10 was used as an index to measure the immune balance of Th1/Th2. Univariate and multivariate logistic regression were performed to analyze the data and then to screen the predicting indicators of cervical cancer. Results Univariate analysis showed that HR-HPV DNA,IL-2,IL-4,IL-6,IL-10,IFN-γ,TNF-ɑ and TNF-ɑ/IL-10 were significantly different between CIN and cervical cancer groups(P<0. 05),which could be used as a risk factor for predicting cervical cancer. Multivariate logistic regression analysis showed that IL-10,IFN-γ,TNF-ɑ,TNF-ɑ/IL-10 were the influencing factors of cervical cancer. The regression model fitted goodness test was Nagelkerke(R2= 0. 982),the pre-judgment rate for CIN was 99. 5% ,the pre-judgment rate of cervical cancer was 100% ,and the total positive rate was 99. 7% ,suggesting good fitting effect was good and the prediction accuracy was high. Conclusion CINⅠand CINⅡhave abnormal expression of Th cytokine,but they do not affect Th1/Th2 balance. Th1/Th2 imbalance in CINⅢ stage and Th2 dominant expression promote the occurrence of cervical cancer. Based on the regression model for predicting cervical carcinogenesis,cervical immunity caused inhibitory microenvironment by local immune imbalance is the key link in HR-HPV persistent infection and cervical cancer,and has nothing to do with HR-HPV DNA.
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Objective To explore the relationship between abnormal expression of fragile histidine triad (FHIT) gene and methyl-CpG-binding protein 2 (MeCP2) as well as their interaction on cervical cancerization.Methods A total of 73 patients with cervical squamous cell carcinoma (SCC),113 patients with cervical intraepithelial neoplasia (CIN Ⅰ,n =45;CIN Ⅱ/Ⅲ,n=68) and 60 women with normal cervix (NC) were included in the study.Real time PCR and Western blot were performed to detect the expression levels of mRNA and protein about FHIT and MeCP2,respectively.The methylation status of FHIT gene CpG island was tested by methylation-specifc PCR (MSP).Kruskal-Wallis H test,x2 test,trend x2 test and Spearman correlation analysis were conducted with software SPSS 20.0.The interaction was evaluated by generalized multifactor dimensionality reduction (GMDR) model.Results With the deterioration of cervical lesion,the methylation rates of FHIT gene CpG island (x2=18.64,P＜0.001;trendx2=18.08,P＜0.001) increased gradually,while the expression levels of FHIT mRNA (H=27.32,P＜0.001;trendx2=12.65,P＜0.001) and protein (H=47.10,P＜0.001;trendx2=29.79,P＜0.001) decreased gradually.There was a negative correlation between the methylation rates of FHIT gene CpG island and the expression level of FHIT protein (r=-0.226,P＜0.001).The levels of MeCP2 mRNA (H=26.19,P＜0.001;trend x2=11.81,P=0.001) and protein (H=69.02,P＜ 0.001;trend x2 =47.44,P＜ 0.001) increased gradually with the aggravation of cervical lesions.There was a positive correlation between the expression level of MeCP2 protein and the FHIT mRNA Ct ratio (r=0.254,P＜0.001).Expression of proteins were negatively correlated between MeCP2 and FHIT (r=-0.213,P=0.001).The results analyzed by GMDR model showed that there were interactions among high MeCP2 protein expression,the CpG island methylation of FHIT and mRNA and protein expression in CIN Ⅱ/Ⅲ group,and among high MeCP2 mRNA and protein expression,the CpG island methylation of FHIT and low mRNA and protein expression in SCC group.Conclusion High expression of MeCP2 mRNA and protein,the CpG island methylation and low mRNA and protein expression of FHIT could increase the risk of cervical carcinogenesis,and there might be a synergistic effect on cervical carcinogenesis.
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Objective To investigate the association between fragile histidine triad (FHIT) gene methylation,abnormal protein expression and HPV16 infection as well as their interactions in cervical carcinogenesis.Methods A total of 108 patients with normal cervical (NC),142 cases of cervical intraepithelial neoplasia (CIN1,n=72;CIN2 +,n=70),and 100 new cases of cervical squamous cell carcinoma (SCC) were chosen from the Shanxi Tumor Hospital,Second Hospital of Shanxi Medical University,Maternal and Child Health Center in Taiyuan and Jiexiu during September 2009 and March 2011.HPV16 was detected by multiple PCR.FHIT methylation and protein expression levels were detected by methylation specific PCR (MSP) and Western Blot,respectively.All the data were performed with SPSS 20.0 statistical softvare.Differences among groups were assessed by Chi-square and Kruskal-Wallis tests.The interaction effects were evaluated by additive model.Results The prevalence rates of HPV16 infection in CIN1 (45.8％),CIN2+ (68.6％) and SCC (73.0％) were significantly higher than that in NC (28.7％,P＜0.001).In NC,CIN1,CIN2+ and SCC groups,the FHIT gene methylation rates were 3.7％,13.9％,21.4％ and 38.0％ while the protein expression levels were 1.255 ± 0.130,1.184 ± 0.172,1.133 ± 0.126 and 1.099 ± 0.148,respectively.Differences among the groups were statistical significant (P＜0.001).With increasing degrees of cervical lesions,the HPV16 infection rate (x2=47.623,P＜0.001),FHIT methylation rate (x2=40.147,P＜0.001) and the rate of FHIT protein low expression (x2=65.098,P＜0.001) were all gradually increasing.There appeared positive additive interaction between FHIT methylation,FHIT protein low expression and infection of HPV16.Conclusion Hypermethylation of FHIT gene,low expression of FHIT protein and HPVI6 infection could increase the risk of cervical cancer and precancerous lesions.These results suggested that there might be synergistic action between FHIT gene hypermethylation and HPV16 infection in the progression of cervical cancer and the same was true between the low expression of FHIT protein and HPV 16 infection.
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Objective To investigate the association between fragile histidine triad (FHIT) gene methylation,abnormal protein expression and HPV16 infection as well as their interactions in cervical carcinogenesis.Methods A total of 108 patients with normal cervical (NC),142 cases of cervical intraepithelial neoplasia (CIN1,n=72;CIN2 +,n=70),and 100 new cases of cervical squamous cell carcinoma (SCC) were chosen from the Shanxi Tumor Hospital,Second Hospital of Shanxi Medical University,Maternal and Child Health Center in Taiyuan and Jiexiu during September 2009 and March 2011.HPV16 was detected by multiple PCR.FHIT methylation and protein expression levels were detected by methylation specific PCR (MSP) and Western Blot,respectively.All the data were performed with SPSS 20.0 statistical softvare.Differences among groups were assessed by Chi-square and Kruskal-Wallis tests.The interaction effects were evaluated by additive model.Results The prevalence rates of HPV16 infection in CIN1 (45.8％),CIN2+ (68.6％) and SCC (73.0％) were significantly higher than that in NC (28.7％,P＜0.001).In NC,CIN1,CIN2+ and SCC groups,the FHIT gene methylation rates were 3.7％,13.9％,21.4％ and 38.0％ while the protein expression levels were 1.255 ± 0.130,1.184 ± 0.172,1.133 ± 0.126 and 1.099 ± 0.148,respectively.Differences among the groups were statistical significant (P＜0.001).With increasing degrees of cervical lesions,the HPV16 infection rate (x2=47.623,P＜0.001),FHIT methylation rate (x2=40.147,P＜0.001) and the rate of FHIT protein low expression (x2=65.098,P＜0.001) were all gradually increasing.There appeared positive additive interaction between FHIT methylation,FHIT protein low expression and infection of HPV16.Conclusion Hypermethylation of FHIT gene,low expression of FHIT protein and HPVI6 infection could increase the risk of cervical cancer and precancerous lesions.These results suggested that there might be synergistic action between FHIT gene hypermethylation and HPV16 infection in the progression of cervical cancer and the same was true between the low expression of FHIT protein and HPV 16 infection.
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Allelic deletions involving the short arm of chromosome 3(3p13-21.1) have been observed frequently in cervical carcinomas. Recently the fragile histidine triad(FHIT) gene was cloned and mapped to this chromosomal region(3p14.2). From various studies involving tumor cell lines and primary cancers, the FHIT gene has been presumed to be a candidate for tumor suppressor gene involving various tumors. In FHIT gene, the most common aphidicolin-inducible fragile site, FRA3B exists and the FRA3B has been considered as a region of the spontaneous integration site of HPV 16. In order to elucidate the role of the FHIT in carcinogenesis of cervical cancer, this study was designed to investigate both the expression of FHIT protein in normal, preinvasive and invasive cancer samples employing immunohistochemical study and allelic loss of FHIT gene locus against several microsatellite markers employing the PCR analysis. Immunohistochemical studies of FHIT protein revealed following features. In normal ectocervical squamous epithelium, the expression of FHIT was relatively weak and confined to the basal layer, but in normal endocervical glandular epithelium it was very strong. The expression of FHIT was reduced as the tumor progressed from early lesion to invasive cancer. The koilocytosis was associated with diminished expression of FHIT protein. The study of allelic loss of FHIT gene locus was undertaken against two intragenic (D3S1300, D3S1234) and one extragenic (D3S1295) microsatellite markers. The 5th intron, D3S1300, showed allelic change in 6 of 15 assays and 7th intron, D3S1234 showed allelic change in 10 of 29 assays. There was no apparent LOH from 29 assays in D3S1295. In conclusion, the expression of FHIT protein was markedly reduced or absent in cervical squamous cell carcinoma and the chromosome breakage in FHIT region might be related to the diminished expression of FHIT. On the basis of the reduced expression of FHIT and its encompassment of FRA3B region, it is suggested that disruption of FHIT, a putative tumor suppressor gene, might be the mechanism by which HPV infection enhances cervical tumorigenesis and clonal outgrowth.