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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Episomal integration is a critical event in human papillomavirus (HPV)-related oncogenesis, although little information is currently available concerning the effect of integration on the host transcriptome. We have used expression microarrays to investigate the effect of integration of HPV16 on gene expression in cervical keratinocytes, using the unique cell line model W12. W12 was generated from a cervical low-grade squamous intraepithelial lesion "naturally" infected with HPV16 and at low passage contains approximately 100 HPV16 episomes/cell. With passage in vitro, integration of viral episomes is associated with the development of phenotypic and genomic abnormalities resembling those seen in cervical neoplastic progression in vivo. We have used the Affymetrix U95A oligonucleotide array that contains probes for 12,600 human transcripts and have identified 85 genes from a range of host cell pathways that show changes in expression levels after integration of HPV16. Whereas some of the genes have previously been implicated in HPV-related oncogenesis in vivo, we have also identified a range of genes not previously described as being involved in cervical neoplastic progression. Interestingly, integration is associated with up-regulation of numerous IFN-responsive genes, in comparison with a baseline of episomally infected cells. These genes include p48, a component of the primary regulator of the IFN response pathway, IFN-stimulated gene factor 3. The physical state of high-risk HPV may substantially influence the response to IFN in infected keratinocytes.
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PMID:Changes in cervical keratinocyte gene expression associated with integration of human papillomavirus 16. 1246 Sep 13

Although the members of the epidermal growth factor receptor family ERBB2 and EGFR are important therapeutic targets in the treatment of malignant neoplasias, little is known about their role in cervical carcinogenesis. Our objective was to evaluate the dysfunction of ERBB2 and EGFR at the gene copy number and protein expression level in neoplastic lesions of the uterine cervix with the aim of obtaining information about its role in cervical carcinogenesis and their possible use as therapeutic targets in these diseases. We studied gene amplification and protein expression of ERBB2 and EGFR and their relationship with Ki67, p16 and p53 and HPV presence in 22 normal/benign (N/B) cervices, 20 low-grade squamous intraepithelial lesions (LSILs), 70 high-grade SILs (HSILs) and 32 invasive squamous cervical carcinomas (ISCCs). No cases showed selective amplification of ERBB2 or EGFR but corresponding chromosome-specific probes displayed chromosome 17 and 7 polyploidy associated with the grade of the lesion (p<0.0001 and p=0.004, respectively) and with the positive expression of Ki67 and p16 (p<0.01). Concurrent polyploidy for both chromosomes was statistically related (p<0.0001). ERBB2 immunohistochemical expression was not observed in any of the study cases except for one ISCC but EGFR was associated with higher-grade lesions (N/B plus LSIL 21.4% vs. HSIL plus ISCC 45.5%; p=0.007). No association was observed between EGFR expression and that of cell-cycle markers or HPV presence. Increased copy number of EGFR and ERBB2 is due to polyploidy of 7 and 17 chromosomes, this being a phenomenon associated with lesion severity and with an increase in the expression of cell-cycle markers. EGFR, but not ERBB2, is expressed in precursor lesions of squamous cervical neoplasia and is related to the neoplastic progression but not to proliferation marker expression and therefore ERBB2 and this calls into question the usefulness of ERBB2 as a therapeutic target.
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PMID:Gene amplification and immunohistochemical expression of ERBB2 and EGFR in cervical carcinogenesis. Correlation with cell-cycle markers and HPV presence. 2382 64

Human Papillomavirus is the major etiological agent in the development of cervical cancer but not a sufficient cause. Despite significant research, the underlying mechanisms of progression from a low-grade squamous intraepithelial lesion to high grade squamous intraepithelial lesion are yet to be understood. Deregulation of viral gene expression and host genomic instability play a central role in virus-mediated carcinogenesis. Key events such as viral integration and epigenetic modifications may lead to the deregulation of viral and host gene expression. This review has summarized the available literature to describe the possible mechanism and role of viral integration in mediating carcinogenesis. HPV integration begins with DNA damage or double strand break induced either by oxidative stress or HPV proteins and the subsequent steps are driven by the DNA damage responses. Inflammation and oxidative stress could be considered as cofactors in stimulating viral integration and deregulation of cellular and viral oncogenes during the progression of cervical carcinoma. All these events together with the host and viral genetic and epigenetic modifications in neoplastic progression have also been reviewed which may be relevant in identifying a new preventive therapeutic strategy. In the absence of therapeutic intervention for HPV-infected individuals, future research focus should be directed towards preventing and reversing of HPV integration. DNA damage response, knocking out integrated HPV sequences, siRNA approach, modulating the selection mechanism of cells harboring integrated genomes and epigenetic modifiers are the possible therapeutic targets.
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PMID:Molecular mechanisms of HPV mediated neoplastic progression. 2793 97

Nicotinamide N-methyltransferase (NNMT) is a cytosolic enzyme, overexpressed in various human malignancies. It is associated with cancer progression and resistance to treatment. The role of NNMT in cervical cancer has not been studied thus far. We aimed to evaluate expression of NNMT in cervical squamous cell carcinoma (SCC) and investigate its clinical significance. NNMT expression was assayed by use of immunohistochemistry in 61 cases of SCC, 11 cases of high-grade squamous intraepithelial lesion, 17 cases of low-grade squamous intraepithelial lesion, and 51 benign cervical tissues. NNMT immunoreactivity was scored based on staining intensity and percentage of positively stained cells. The expression of NNMT was significantly higher in SCC than in benign tissue, low-grade squamous intraepithelial lesion, and high-grade squamous intraepithelial lesion (P<0.001). NNMT expression in benign tissue was significantly lower than in low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion. When stratified according to stage, NNMT expression was significantly higher in patients with stage III and IV than those in stage I and II disease (P=0.009). For all stages, patients with metastatic pelvic or para-aortic lymph nodes had significantly higher NNMT expression than patients without nodal involvement (P=0.001). Although preliminary, this is the first study to detect overexpression of NNMT in SCC and increased expression associated with advanced stage and metastatic lymph nodes. NNMT should be investigated further in cervical cancer as a potential therapeutic target and a prognostic indicator.
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PMID:Expression and Clinical Significance of Nicotinamide N-Methyltransferase in Cervical Squamous Cell Carcinoma. 3103 1

Cervical cancer is the most prevalent cancer among women in India. The main cause of cervical cancer is persistent human papilloma viral (HPV) infection. HPV inactivates the pRb tumour suppressor protein; thus p16 expression, which is controlled by a negative feedback mechanism, is relatively increased. Galectin-3 is directly and indirectly connected to cancer cell activity and contributes to oncogenesis, angiogenesis, cancer progression and metastasis. Thus, the aim of this study was to study the expression of p16 and galectin-3 in Cervical Intraepithelial Neoplasia (CIN) and Squamous Cell Carcinoma (SCC) and to correlate p16 and galectin-3 expression. On hundred and eighteen newly-diagnosed untreated cases of CIN and SCC of uterine cervix were included in the study. Expression of p16 and galectin 3 was more pronounced in invasive SCC and High-grade Intraepithelial Lesion (HSIL), as compared to Low-grade Intraepithelial Lesion (LSIL).Thus, it may be used in clinical setting to monitor cervical lesions and to predict their progression. Impact statement What is already known on this subject? p16 overexpression is a surrogate biomarker of HPV infection and useful in evaluating HPV-associated squamous and glandular neoplasia of the lower gynaecologic tract. Increased galectin-3 expression is seen in SCC cervical, with less consistent results in CIN. What do the results of this study add? The results of our study adds to the growing literature that p16 and galectin-3 expression have direct statistically significant correlation with a degree of dysplasia and SCC cervix. Expression of p16 and galectin-3 was more pronounced in invasive SCC and high-grade intraepithelial lesion (HSIL), as compared to low-grade intraepithelial lesion (LSIL). What are the implications of these findings for clinical practice and/or further research? This correction of p16 and galectin-3 expression with degree of dysplasia and SCC cervix can be used for screening and early detection of cervical lesions and thus aid their early treatment and increased survival.
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PMID:The expression of p16 and galectin-3 in cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC) uterine cervix. 3307 44