Measurement of Brn-3a levels in Pap smears provides a novel diagnostic marker for the detection of cervical neoplasia

Sindos, Michael; Ndisang, Daniel; Pisal, Narendra; Chow, Carl; Singer, Albert; Latchman, David S.

doi:10.1016/s0090-8258(03)00261-0

Cited by 10 publications

(12 citation statements)

References 37 publications

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“…To evaluate the effect of Brn-3a on the different HPV-16 variants, we utilized an RT-PCR assay, which we have previously used to successfully measure Brn-3a and HPV E6 mRNA expression in cervical biopsies and cervical smears (Ndisang et al, 1998(Ndisang et al, , 2000Sindos et al, 2003) with Brn-3a mRNA levels correlating well with Brn-3a protein levels when sufficient material is available for these to be measured (Ndisang et al, 1998). The levels of Brn-3a and HPV E6 mRNA were measured in a series of colposcopy samples, which had previously been typed according to their variation in the region of the HPV-16 genome encoding E5 (Bible et al, 2000).…”

Section: Resultsmentioning

confidence: 99%

Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a

et al. 2005

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The Brn-3a POU family transcription factor is overexpressed in human cervical carcinoma biopsies and is able to activate expression of the human papilloma virus type 16 (HPV-16) upstream regulatory region (URR), which drives the expression of the E6 and E7 oncoproteins. Inhibition of Brn-3a expression in human cervical cancer cells inhibits HPV gene expression and reduces cellular growth and anchorage independence in vitro as well as the ability to form tumours in vivo. Here, we show that Brn-3a differentially regulates different HPV-16 variants that have previously been shown to be associated with different risks of progression to cervical carcinoma. In human cervical material, Brn-3a levels correlate directly with HPV E6 levels in individuals infected with a high risk variant of HPV-16, whereas this is not the case for a low-risk variant. Moreover, the URRs of high-and intermediate-risk variants are activated by Brn-3a in transfection assays, whereas the URR of a low-risk variant is not. The change of one or two bases in a lowrisk variant URR to their equivalent in a higher-risk URR can render the URR responsive to Brn-3a and vice versa. These results help explain why the specific interplay between viral and cellular factors necessary for the progression to cervical carcinoma only occurs in a minority of those infected with HPV-16.

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Section: Resultsmentioning

confidence: 99%

Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a

et al. 2005

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“…To determine the levels of the mRNA encoding the ongogenic E6 product and the cellular transcription factor Brn-3a in the cervix of both smokers and nonsmokers, we used our previously defined reversetranscriptase PCR procedure (Sindos et al, 2003a;Ndisang et al, 2006a, b). We observed that the mean E6 mRNA for smokers was higher than that of nonsmokers (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…To identify the specific HPV-16 variant that the patients who smoked or did not smoke were infected with, we used a RFLP (Restriction Fragment Length Polymorphism) assay, which was adapted from the study by Bible et al (2000), and have used previously to type the DNA of different HPV variants in clinical samples (Sindos et al, 2003a;Ndisang et al, 2006a). Thus, we were able to identify the type of HPV-16 variant each of the women were infected with (Table 1).…”

Section: Resultsmentioning

confidence: 99%

The cellular transcription factor Brn-3a and the smoking-related substance nicotine interact to regulate the activity of the HPV URR in the cervix

et al. 2010

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The cellular transcription factor Brn-3a differentially regulates different human papilloma virus (HPV)-16 variants that are associated with different risks of progression to cervical carcinoma in infected humans. The upstream regulatory regions (URRs) of high-and intermediate-risk HPV-16 variants are activated by the cellular transcription factor Brn-3a, whereas the URR of a low-risk HPV-16 variant is not. In this study, we show in transfection assays that Brn-3a and the smoking-related substance nicotine produce stronger responsiveness of the URR of the low-and high-risk variants than with either factor alone, but not the intermediate-risk variant. We determined that this synergistic activity of Brn-3a/ nicotine is due to two nucleotide differences in the URR, crucial for oncogenic E6/E7 transactivation. Mutant constructs in which the nucleotide residues were substituted alter Brn-3a/nicotine responsiveness. Importantly, women smokers with high levels of Brn-3a infected with low-or high-risk HPV-16 variants have augmented E6 levels, and were more frequently diagnosed with higher grades of cervical intraepithelial neoplasia (CIN) and cancer, as compared with non-smokers who were infected with similar variants and expressed similar levels of Brn3a. Therefore, this study defines the specific interplay between the cellular transactivator Brn-3a, the environmental smoking-related substance nicotine and specific HPV variants in cervical carcinogenesis, and thus helps to explain why some women are susceptible to rapid CIN progression and cancer and others are not.

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“…hTERT gene or TERC gene were amplifi ed with progression of high-grade CIN to invasive cervical cancer; the copy number of telomerase gene seemed to be increased as a results of aneuploidy or genomic integration of oncogenic HPV genome; gain of telomerase gene can indicate genetic events in the progression to invasive cancer [68][69][70] Brn-3a RT-PCR Signifi cant correlation between Brn-3a expression and the grade of cervical lesion; Brn-3a assay may help improve accuracy of conventional cytology [72,73] CDC accuracy to detect high-grade CIN [46,47] . The increased proliferation identified with Ki-67 staining must be interpreted with caution when examining inflammatory lesions, and Ki-67 staining can show increased positivity during the luteal phase of menstrual cycle and pregnancy [48] .…”

Section: Immunohistochemical Staining Of Cell Proliferation Markersmentioning

confidence: 99%

Emerging biomarkers in the detection, diagnosis and management of cervical dysplasia and carcinoma

Bae

Park

2007

Expert Opinion on Medical Diagnostics

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Despite the success of widespread screening, cervical cancers continue to occur. Recently, the role of human papillomavirus (HPV) in cervical carcinogenesis has been firmly established. HPV prophylactic vaccines are expected to eradicate ∼ 70% of cervical cancers. An HPV test was demonstrated to improve the sensitivity of cytology and prolong the screening interval safely. Type-specific HPV testing will play an important role in the detection and follow up of cervical neoplastic lesions, as well as monitoring the efficacy of HPV vaccines. The combined use of cell proliferation markers with cytology can improve sensitivity, and some molecular markers seem to be related to the degree of dysplasia. Further studies are needed to evaluate the use of biomarkers in clinical settings.

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Measurement of Brn-3a levels in Pap smears provides a novel diagnostic marker for the detection of cervical neoplasia

Cited by 10 publications

References 37 publications

Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a

Differential regulation of different human papilloma virus variants by the POU family transcription factor Brn-3a

The cellular transcription factor Brn-3a and the smoking-related substance nicotine interact to regulate the activity of the HPV URR in the cervix

Emerging biomarkers in the detection, diagnosis and management of cervical dysplasia and carcinoma

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