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IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions.

ABSTRACT: Human papillomavirus (HPV) plays a crucial role in cervical cancer etiology. However, not all HPV-infected women develop cancer, indicating that additional cellular factors facilitate carcinogenesis. The aim of this study was to analyze the expression profile of insulin-like growth factor 1 (IGF1) isoforms in the context of FOX2, SP1 and IGF1 receptor (IGF1R) expression during HPV-dependent cervical carcinogenesis. One hundred and nine epithelial tissue samples from women with pre-cancerous and cancer lesions of the cervix were analyzed. HPV DNA was identified by PCR, and real-time PCR was used to quantify the expression levels of the analyzed genes. All IGF1 mRNA splicing isoforms were up-regulated in pre-cancerous cells, and a shift in the balance towards mitogenic IGF1Eb was observed in the cancer samples. IGF1 expression was controlled mainly by the P1 promoter, and an increase in P2 usage was observed in the cancer. Correlations between IGF1 mRNA splicing isoforms and the FOX2 splicing factor, as well as P1/P2 activity and SP1 transcription factor expression levels were detected. No correlation was observed between the expression of IGF1 and its receptor IGF1R. Our results suggest that IGF1, in particular its splicing profile, may be an additional prognostic factor in cervical carcinogenesis.

SUBMITTER: Koczorowska MM

PROVIDER: S-EPMC3440635 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions.

Koczorowska Maria Magdalena MM Kwasniewska Anna A Gozdzicka-Jozefiak Anna A

Experimental and therapeutic medicine 20101202 1

Human papillomavirus (HPV) plays a crucial role in cervical cancer etiology. However, not all HPV-infected women develop cancer, indicating that additional cellular factors facilitate carcinogenesis. The aim of this study was to analyze the expression profile of insulin-like growth factor 1 (IGF1) isoforms in the context of FOX2, SP1 and IGF1 receptor (IGF1R) expression during HPV-dependent cervical carcinogenesis. One hundred and nine epithelial tissue samples from women with pre-cancerous and ...[more]

PMID: 22977483

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Project description:Continuous expression of E6- and E7-oncogenes of high-risk human papillomavirus (HPV) types is necessary for the development and maintenance of the dysplastic phenotype. The aim of the study was to determine the sensitivity and specificity of the APTIMA HPV mRNA assay (Hologic) in predicting future development of high-grade cervical intraepithelial neoplasia (CIN) among high-risk HPV-DNA-positive women with atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous epithelial lesion (LSIL) cytology.Archived SurePath cervical samples of women ≥ 35 years of age with high-risk HPV DNA-positive ASCUS (n = 211) or LSIL, (n = 131) were tested for the presence of high-risk HPV E6/E7 mRNA using the APTIMA HPV assay, and the women were monitored for development of histopathologically verified CIN2+.Twenty-nine percent (61/211) of the women in the ASCUS group, and 34.3% (45/131) in the LSIL group developed CIN2+ within 4.5 years of follow-up. The prevalence of HPV mRNA was 90.0% (95% CI 85.9-94.0) among women with ASCUS and 95.4% (95% CI 91.8-99.0) among women with LSIL. The presence of HPV E6/E7 mRNA was associated with future development of CIN2+ among women with ASCUS and LSIL (p=0.02). The mRNA assay demonstrated high sensitivity in predicting future CIN2+ and CIN3 for index ASCUS (96.7%; 95% CI 87.6-99.4 and 100%; 95% CI 82.2-100, respectively) and LSIL (97.8%, 95% CI 86.8-99.9 and 100%, 95% CI 79.9-100, respectively). The corresponding specificity was low, 12.7% (95% CI 7.9-19.3) and 5.8% (95% CI 2.2-13.6), for future CIN2+, respectively. The negative predictive value of the HPV mRNA assay for detecting future CIN3 was 100%, since no mRNA-negative woman developed CIN3 (0/27) as compared to 13.6% (43/315) of the mRNA-positive women (p = 0.03).The APTIMA mRNA assay demonstrated high sensitivity but low specificity in predicting future CIN2+ among women with minor cytological abnormalities. The assay had high negative predictive value for future CIN3, indicating that HPV-mRNA-negative women are at low risk of progression to high grade CIN.

Project description:More information is needed about time between sexual initiation and human papillomavirus (HPV) infection and development of cervical precancer.The objectives were to investigate the time between first sexual activity and detection of first cervical HPV infection or development of first cervical intraepithelial neoplasia (CIN), and associated factors in women from the double-blind, multinational, 4-year PATRICIA trial. PATRICIA enroled women aged 15-25 years with no more than 6 lifetime sexual partners. Women were randomized 1:1 to the HPV-16/18 AS04-adjuvanted vaccine or to control, but only women from the control arm who began sexual intercourse during the study or within 6 months before enrolment, and had no HPV infection detected before the recorded date of their first sexual intercourse, were included in the present analysis. The time between onset of sexual activity and detection of the first cervical HPV infection or development of the first CIN lesion was analyzed using Kaplan-Meier and univariate and multivariable Cox proportional-hazards models.A total of 9337 women were enroled in the control arm of PATRICIA of whom 982 fulfilled the required inclusion criteria for analysis. A cumulative total of 28%, 44%, and 62% of the subjects had HPV infection within 12, 24, and 48 months, respectively. The overall incidence rate was 27.08 per 100 person-years. The most common oncogenic types associated with 6-month persistent infection were HPV-16 (incidence rate: 2.74 per 100 person-years), HPV-51 (2.70), HPV-52 (1.66), HPV-66 (1.14), and HPV-18 (1.09). Increased infection risk was associated with more lifetime sexual partners, being single, Chlamydia trachomatis history, and duration of hormone use. CIN1+ and CIN2+ lesions were most commonly associated with HPV-16, with an overall incidence rate of 1.87 and 1.07 per 100 person-years, respectively. Previous cervical HPV infection was most strongly associated with CIN development.More than 25% of women were infected with HPV within 1 year of beginning sexual activity. Without underestimating the value of vaccination at older ages, our findings emphasize its importance before sexual initiation.clinicaltrials.gov: NCT00122681 .

Project description:BackgroundCervical cancer is the leading cause of cancer related deaths among women in India. Limited reports are available for Notch-1 and Notch-3 protein in cervical carcinoma, which play crucial role in cell proliferation, differentiation, and apoptosis.MethodsThis study was designed to evaluate the role of Notch-1 and Notch-3 with context to HPV infection in cervical carcinoma. A total of 168 tissue biopsy samples comprising of tumor specimens (n = 98), precancer (n = 30) and non-neoplastic cervical tissues (n = 40) were screened for HPV infection by PCR and expression of Notch-1 and Notch-3 protein by Immunohistochemistry and Immunoblotting.Results80% (24/30) were found to be positive for HPV in precancer and 86.7% (85/98) in cancer patients. Notch-1 expression of precancer and cancer cases was found to be significantly down-regulated with severity of disease in nuclear (3.43±0.29; 2.04±0.19, p = 0.0001, p = 0.0001) and cytoplasm (3.07±0.29; 2.29±0.17, p = 0.0001, p = 0.0001) obtained from different stages as compared to normal cervix tissue (5.40±0.19, 4.97±0.15; p<0.001; p<0.001). However, Notch-3 expression of above cases was significantly up-regulated with severity of disease and showed intense nuclear (4.17±0.39; 4.74±0.18, p = 0.0001, p = 0.0001) and cytoplasm (3.67±0.36; 4.48±0.18, p = 0.0001, p = 0.0001) of different stages as compared to normal cervix tissue (0.95±0.20, 0.70±0.20; p<0.001; p<0.001) respectively.ConclusionsThese findings suggest that Notch-1 and Notch-3 may play an important role with synergistic effect of HPV in regulating development and proliferation of cervical cancer through the deregulation of Notch signalling. This study also shows the clinical utility of both proteins which may be used as predictable biomarkers in diagnosing different histological sub-types of HPV associated cervical cancer. Nevertheless, abnormal activation of this pathway may provide legitimate targets for cervical cancer therapy.

Dataset Information

IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions.

Publications

IGF1 mRNA isoform expression in the cervix of HPV-positive women with pre-cancerous and cancer lesions.

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