Overexpression of VEGF and TGF-β1 mRNA in Pap smears correlates with progression of cervical intraepithelial neoplasia to cancer: Implication of YY1 in cervical tumorigenesis and HPV infection

Abstract

Abstract. The screening of neo-angiogenesis related gene expression has uncovered many disrupted molecular pathways which may significantly confer to malignant transformation of various cell types including cervical cells. The objective of the present study was to delineate whether changes in certain gene expression profiles during the malignant conversion of the uterine cervix can be potentially used to predict the clinical course and outcome of the cervical pathology. Total RNA was isolated from Pap smears obtained from healthy females or patients diagnosed with low-grade squamous cervical intraepithelial lesions (LG-SIL), high-grade (HG)-SIL or cervical carcinoma. VEGF, TGF-ß1 and YY1 mRNA expression levels were assessed by QRT-PCR. Confirmation of YY1 protein discrepancy among cervical tissues of different histopathology was performed by immunohistochemistry. All tested genes showed statistically significant expression variations among the indicated groups. VEGF and TGF-ß1 mRNA overexpression was found to be associated with progression from low-grade to high-grade cervical intraepithelial neoplasia (CIN), while YY1 showed constitutively elevated transcript levels in CIN and cervical cancer compared to controls. At the protein level YY1 was also overexpressed in HG-SIL and cancer tissues compared to LG-SIL. Both YY1 transcript and protein overexpression were associated with HPV18-or HPV16-infected samples. Spearman analysis revealed a co-expression pattern for VEGF and TGF-ß1 mRNAs in normal cervix and LG-SIL; however, YY1 expression correlated negatively with VEGF and TGF-ß1 transcript levels upon the onset of the cervical neoplastic transformation. Our findings provide for the first time evidence for the implication of YY1 in uterine cervix carcinogenesis and suggest that VEGF, TGF-ß1 and YY1 could be useful biomarkers of cervical malignant transformation as well as potential targets for therapeutic approaches.

Yin Yang 1 overexpression in diffuse large B-cell lymphoma is associated with B-cell transformation and tumor progression

“…The putative role of YY1 in tumorigenesis is supported by its known interaction in the cell cycle regulation 4 and, accordingly, many studies were conducted to evaluate the involvement of YY1 in several solid tumor types. [14][15][16][17][18][19] In this study we have provided evidence that YY1 is expressed at significantly higher levels in high-grade lymphomas, including Burkitt's Lymphoma and DLBCL, when compared to normal B cells. DLBCL is the most frequent non-Hodgkin's lymphoma subtype, accounting for 30% to 35% of all lymphoma cases.…”

The involvement of the transcription factor Yin Yang 1 in cancer development and progression

“…In addition, the authors showed that the increase of YY1 at both transcript and protein levels were associated with the presence of Human Papilloma Virus (HPV) infection indicating that YY1 may play an important role in the malignant transformation. 22 YY1 overexpression has been documented also in human osteosarcoma. 23 The authors, using different approaches, demonstrated that YY1 is overexpressed in osteosarcoma cell lines and tissues compared to normal osteoblastic cells with a predominant localization in the nucleus.…”

Yin Yang-1 inhibits tumor cell growth and inhibits p21WAF1/Cip1 complex formation with cdk4 and cyclin D1

“…Elevated YY1 protein levels are associated with a number of cancer types such as high-grade squamous cervical intraepithelial lesions, cervical cancer and HPV infection of the cervix (16). This has led to the suggestion that YY1 may serve as a diagnostic and prognostic tumor marker, and a drug target in cancer therapy (11).…”