Quercetin elevates p27Kip1 and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1

Our previous work with primary bovine fibroblasts demonstrated that quercetin, a potent mutagen found in high levels in bracken fern (Pteridium aquilinum), arrested cells in G1 and G2/M, in correlation with p53 activation. The expression of bovine papillomavirus type 4 (BPV-4) E7 overcame this arrest and lead to the development of tumorigenic cells lines (Beniston et al., 2001). Given the possible link between papillomavirus infection, bracken fern in the diet and cancer of the upper gastrointestinal (GI) tract in humans, we investigated whether a similar situation would occur in human cells transformed by human papillomavirus type 16 (HPV-16) oncoproteins. Quercetin arrested primary human foreskin keratinocytes in G1. Arrest was linked to an elevation of the cyclin-dependent kinase inhibitor (cdki) p27Kip1. Expression of the HPV16 E6 and E7 oncoproteins in transformed cells failed to abrogate cell cycle arrest. G1 arrest in the transformed cells was also linked to an increase of p27Kip1 with a concomitant reduction of cyclin E-associated kinase activity. This elevation of p27Kip1 was due not only to increased protein half-life, but also to increased mRNA transcription

A high frequency of human papilloma virus (HPV) DNA type 16 in biopsies of cervical squamous cell neoplasia of Uygur women

Cervical carcinoma ranks among the most common tumors worldwide and is especially prevalent in the developing world. Strong evidence supports the role of human papillomavirus (HPV) infection in the genesis of these tumors. The authors examined 65 cervical neoplasias from a population of women at particularly high risk for the development of cervical cancer in Western China. HPV DNA analysis consisted of in-situ hybridization (n=65) and polymerase chain reaction (PCR) (n=58) for the detection of HPV types 6, 11, 16, 18, 31, 33, and 35. Both consensus and type-specific primers for HPV types 6, 16, and 18 were used in the PCR studies. Overall, HPV DNA was detected in 76.9% of cases. In-situ hybridization identified HPV DNA in 43.1% of patients. PCR with consensus primers detected HPV DNA in 22.4% of lesions, whereas type-specific primers for the HPV E6 gene demonstrated HPV DNA in 77.6% of cervical tumors. Type-specific PCR was more sensitive than L1 consensus PCR and in-situ hybridization for detection of HPV DNA. Thirty-two (55.2%) cases that were negative by L1 consensus PCR and 21 (32.3%) that were negative by in-situ hybridization were positive by type-specific PCR. Of the 50 cases positive for HPV DNA by one or more of these assays, 94% (n=47) were identified as HPV type 16; 4% (n=2) as HPV 31, 33, or 35; and 2% (n=1) as another, unidentified, HPV type. These data support the role of HPV in the pathogenesis of cervical carcinoma in high-risk women living in Western China. This study represents the first report of HPV analyses in Uygur women with cervical cancer

Cumulate survival curve for 98 women of Uygur ethnicity from Xinjiang, China with cervical carcinoma.

<p>Cumulate survival curve for 98 women of Uygur ethnicity from Xinjiang, China with cervical carcinoma.</p

Expression and Prognostic Value of Aquaporin 1, 3 in Cervical Carcinoma in Women of Uygur Ethnicity from Xinjiang, China

<div><p>Background</p><p>Overexpression of several aquaporins has been reported in different types of human cancer but the role of aquaporins in carcinogenesis has not yet been clearly defined. There is few report concerning role of aquaporins in human cervical carcinogenesis so far. Here, we determined the expression and prognostic value of aquaporin 1, 3 in cervical carcinoma in Chinese women of Uygur ethnicity.</p><p>Methods and Results</p><p>Real-time PCR analyses demonstrated aquaporin 1, 3 mRNA were differentially expressed in cervical carcinoma, CIN 2-3 and mild cervicitis. Immunofluorescent and immunohistochemical analyses demonstrated aquaporin 1 was predominantly localized to stromal endothelial cells in cervical lesions. Aquaporin 3 was localized to the membrane of normal squamous epithelium, CIN and carcinoma cells. Aquaporin 1 and 3 were upregulated in cervical cancer compared to mild cervicitis and CIN2-3 (<i>P</i><0.05); Tumor expression of aquaporin 1, 3 significantly increased in advanced stage disease, and patients with deeper tumor infiltration, lymph node metastases or larger tumor volume (<i>P</i><0.05). Multivariate analysis demonstrated that aquaporin 1, 3 were not independent prognostic factors in cervical carcinoma.</p><p>Conclusion</p><p>Aquaporins may participate in the initiation and progression of cervical carcinoma by promoting tumor growth, invasion or lymph node metastasis. Further study is required to determine whether aquaporins have potential as prognostic factors in cervical cancer.</p></div

Relationship between AQP expression and cumulate survival curve for 98 women of Uygur ethnicity from Xinjiang, China with cervical carcinoma.

<p>A, stratified by expression of AQP1, scored as AQP1 microvessel density (MVD):(1) MVD≤60 (2) MVD>60, P = 0.000; B,stratified by expression of AQP3(1) negative or (2) positive.</p

Analysis of AQP1 and AQP3 expression in cervical lesions 1–4: AQP1 RT-PCR electrophotogram; 1and 2, mild cervicitis; 3, early stage cervical cancer; 4, advanced stage cervical cancer.

<p>5–8: AQP3 RT-PCR electrophotogram; 5 and 6, mild cervicitis; 7, early stage cervical cancer, 8, advanced stage cervical cancer.</p

Multivariate analysis of prognostic factors in cervical cancer in women of Uygur ethnicity.

<p>Note: using Cox proportional hazards mode.</p

Cox univariate analysis of cumulate survival for women of Uygur ethnicity with cervical cancer.

<p>Cox univariate analysis of cumulate survival for women of Uygur ethnicity with cervical cancer.</p