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Tissue tumor marker expression in normal cervical tissue and in cervical intraepithelial neoplasia, for women who are at high risk of human papilloma virus infection, are smokers, contraceptive users or in fertile age
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this research was to study the correlation between tissue tumor marker expression and HR-HPV infection, smoking, hormonal contraceptive use and sex steroids in women with cervical intraepithelial neoplasia or normal epithelium. The study investigated the expression of 11 tumor markers in cervical biopsies obtained from 228 women with different diagnoses ranging from normal cervical epithelium to various stages of CIN. 188 women were recruited at our colposcopy clinic (out-patient surgery, Department of Obstetrics and Gynecology, Falun Hospital) for laser cervical conization or a directed punch biopsy, either because of a vaginal smear (Pap smear) that showed cytological findings suggesting CIN, or because of repeated findings showing atypical squamous cells of undetermined significance (ASCUS). For 40 volunteers, punch biopsies were taken from the normal cervical epithelium. The time period for this study was 2005-2007.

Study I :  228 women, of whom 116 were tested, 64 were positive to HR-HPV. The results showed that Ki67 tumor cell proliferation index was the only marker that independently correlated to both the presence of HR-HPV and the severity of cervical lesions.

Study II:  228 women, of whom 83 were smokers (36, 9%). Smokers showed lower expression of p53, FHIT (tumor suppressor markers) and interleukin-10 .Higher expression of Cox-2 and Ki-67 (tumor proliferation markers).

Study III:  195 women who were premenopausal. There was increased p53 expression (tumor suppressor) in the progestin-IUD users compared to non-users. Decreased IL-10 expression (immunological marker) was observed in both COC users and any progestin-only users.

Study IV: Serum from 80 premenopausal women was available. The main finding was that the increased levels of serum progesterone and estradiol were associated with increased Cox-2 expression (proliferation marker). Serum progesterone and estradiol levels influence cellular and extracellular proteins which have been associated with neoplastic development in normal epithelium and CIN.

Conclusion: The results of these studies support previous epidemiological findings on the role of smoking, contraceptive use and sex steroids as co-factors in development of CIN and that tumor marker expression varies in different grades of CIN.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1137
Keyword [en]
tumor markers, cervical intraepithelial neoplasia, smoking, contraceptive use, sex steroid hormones, HPV infection
National Category
Health Sciences
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:uu:diva-262889ISBN: 978-91-554-9348-6 (print)OAI: oai:DiVA.org:uu-262889DiVA: diva2:855811
Public defence
2015-11-16, Rosénsalen, ingång 95/96, Akademiska sjukhuset, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2015-10-21 Created: 2015-09-22 Last updated: 2015-10-27
List of papers
1. High-Risk HPV Infection and CIN Grade Correlates to the Expression of c-myc, CD4(+), FHIT, E-cadherin, Ki-67, and p16(INK4a)
Open this publication in new window or tab >>High-Risk HPV Infection and CIN Grade Correlates to the Expression of c-myc, CD4(+), FHIT, E-cadherin, Ki-67, and p16(INK4a)
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2011 (English)In: Journal of Lower Genital Tract Disease, ISSN 1089-2591, E-ISSN 1526-0976, Vol. 15, no 4, 280-286 p.Article in journal (Refereed) Published
Abstract [en]

Objective. This study aimed to investigate correlations between a panel of biomarkers/tumor markers and high-risk (HR) human papillomavirus (HPV)-positive versus HR-HPV-negative cervical lesions.

Materials and Methods. The study included 188 women who consecutively attended a colposcopy clinic because of PAP smears suggesting cervical intraepithelial neoplasia (CIN), and 40 women with normal vaginal cytology. Tissue microarray blocks were prepared from representative cervical cone or punch biopsies. Sections were stained for 12 biological markers, previously shown to be relevant in cervical neoplasms, and expression was correlated to the presence or absence of HR-HPV in cervical lesions.

Results. No correlations between expression of biomarkers and HPV status were found in normal epithelium. Expression of c-myc, CD4(+), Ki-67, and p16(INK4a) correlated significantly to HR-HPVYinfected epithelium compared with HR-HPV-negative epithelium. When adjustment was made for CIN grade, only the expression of Ki-67 correlated significantly with HPV status and CIN grade. Human papillomavirus status was stratified to normal epithelium, low-grade CIN, and high-grade CIN. Fragile histidine triad (FHIT), E-cadherin, Rb, Ki-67, and p16(INK4a) expression was significantly increased in HPV-positive tissue by increasing CIN grade. No correlation to tumor marker expression was observed in the HPV-negative tissue. Conclusions. This study described correlations, previously not investigated, between HPV status and tumor marker expression, that is, E-cadherin, Rb, and fragile histidine triad. Surprisingly, p16(INK4a) was not, although Ki-67 expression was, independently correlated to HPV positivity. The results of this study suggest that p16(INK4a) instead correlates independently with increasing CIN grade.

Keyword
human papillomavirus, cervical intraepithelial neoplasia, cervical epithelium, tumor markers
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-160386 (URN)10.1097/LGT.0b013e318215170c (DOI)000295398800005 ()
Available from: 2011-10-24 Created: 2011-10-24 Last updated: 2017-12-08Bibliographically approved
2. Tissue tumor marker expression in smokers, including serum cotinine concentrations, in women with cervical intraepithelial neoplasia or normal squamous cervical epithelium
Open this publication in new window or tab >>Tissue tumor marker expression in smokers, including serum cotinine concentrations, in women with cervical intraepithelial neoplasia or normal squamous cervical epithelium
Show others...
2010 (English)In: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 202, no 6, 579.e1-579.e7 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: The purpose of this study was to investigate correlations between smoking and serum cotinine, respectively, and tumor marker expression in cervical intraepithelial neoplasia (CIN) and normal epithelium. STUDY DESIGN: Women (n = 228) with cervical biopsy specimens that ranged histologically from normal to carcinoma in situ (CIN III) were included. Expression of 11 tumor markers with possible relevance in cervical neoplasms was studied. Smoking habits were recorded, and serum was assessed for cotinine concentrations. RESULTS: No differences were found in tumor marker expression in normal epithelium between smokers and nonsmokers. The tumor suppressors p53 and fragile histidine triad and the immunologic marker interleukin-10 were underexpressed, and the tumor markers cyclooxygenase-2 and Ki-67 were overexpressed in smoking, compared with nonsmoking, women with CIN and particularly in all fertile women. CONCLUSION: The molecular pattern indicates that smoking exerts unfavorable effects in cervical neoplasia. This provides biologic evidence of smoking being a true cofactor in cervical neoplasia.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-126236 (URN)10.1016/j.ajog.2009.11.034 (DOI)000278534200025 ()20060094 (PubMedID)
Available from: 2010-06-07 Created: 2010-06-07 Last updated: 2017-12-12Bibliographically approved
3. Oral contraceptive and progestin-only use correlates to tissue tumor marker expression in women with cervical intraepithelial neoplasia
Open this publication in new window or tab >>Oral contraceptive and progestin-only use correlates to tissue tumor marker expression in women with cervical intraepithelial neoplasia
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2012 (English)In: Contraception, ISSN 0010-7824, E-ISSN 1879-0518, Vol. 85, no 3, 288-293 p.Article in journal (Refereed) Published
Abstract [en]

Background: The study was conducted to investigate correlations between combined oral contraceptive (COC), any progestin-only contraceptive, medicated intrauterine device (MID) or systemic progestin-only (Syst-P) use and tumor marker expression in cervical intraepithelial neoplasia compared to nonusers.

Study Design: One-hundred ninety-five women of fertile age with cervical biopsies ranging histologically from normal epithelium to carcinoma in situ were recruited consecutively. Combined oral contraceptive, Syst-P and MID users were investigated according to the expression of 11 tumor markers.

Results: Overexpression of cyclooxygenase-2 (Cox-2) was observed in COC users, while interleukin 10 was underexpressed. When users of progestogen-only contraceptives were analyzed, there was a lower expression of cytokeratin 10 and interleukin 10. When only MID users were analyzed, a high expression of p53 was found. Expression of Cox-2, p53 and retinoblastoma protein differed between COC and MID users.

Conclusion: The study showed molecular alterations, which, in general, have not been studied previously in COC users and have never been studied in progestogen-only users. These biological events might be involved in epidemiological correlations found between hormonal contraceptive use and cervical neoplasms.

Keyword
Cervical intraepithelial neoplasia, Oral contraceptives, Gestagen, Medicated intrauterine device, Biological markers
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-171406 (URN)10.1016/j.contraception.2011.09.001 (DOI)000300387500012 ()
Available from: 2012-03-20 Created: 2012-03-19 Last updated: 2017-12-07Bibliographically approved
4. Increased Serum Progesterone and Estradiol Correlate to Increased COX-2 Tissue Expression in Cervical Intraepithelial Neoplasia
Open this publication in new window or tab >>Increased Serum Progesterone and Estradiol Correlate to Increased COX-2 Tissue Expression in Cervical Intraepithelial Neoplasia
Show others...
2010 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 30, no 4, 1217-1222 p.Article in journal (Refereed) Published
Abstract [en]

The aim of this study was to To investigate correlations between serum progesterone and serum estradiol levels and expression of tissue tumor markers in cervical intraepithelial neoplasia (CIN) and normal epithelium. Materials and Methods: Eighty women of fertile ages with cervical biopsies ranging histologically from normal to CIN III were included. Expression of eleven tumor markers was studied. Serum levels of progesterone and estradiol were analyzed. Exclusion criterion was hormonal contraceptive use. Results: In normal epithelium, low progesterone levels correlated to expression of epidermal growth factor receptor (EGFR) and CD4+. In initial analyses of CIN, high progesterone levels correlated with expression of retinoblastoma protein, p16 and cyclooxygenase-2 (COX-2), but after adjustment for CIN grade, only correlation to COX-2 expression remained significant. Expression of COX-2 and CD4+ correlated to serum estradiol levels in CIN. Conclusion: Serum levels of progesterone and estradiol appear to correlate with increased COX-2 expression in CIN. In addition, the study shows that evaluation of expression of tumor markers must take into account the grade of CIN.

Keyword
Cervical intraepithelal neoplasia, cervical squamous epithelium, progesterone, estradiol, biological markers
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-135416 (URN)000278686600025 ()20530431 (PubMedID)
Available from: 2010-12-07 Created: 2010-12-06 Last updated: 2017-12-11Bibliographically approved

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