An Analysis of Risk Factors for Developing Hepatocellular Carcinoma in a Group of Hepatitis C Patients with Stage 3 Fibrosis following Interferon Therapy

The risk of Hepatocellular carcinoma (HCC) is high in HCV-infected patients who have biochemically and histologically active chronic hepatitis. To observe the long prognosis of Chronic Hepatitis C (CHC) patients with stage 3 fibrosis (F3), 55 CHC patients after initial Interferon (IFN) therapy were followed up for up to 12 years (average 9.8 ± 2.3 years). According to the annual average alanine aminotransferase (ALT) levels, patients were grouped into, low (ALT ≦ 30 IU/l); moderate (ALT >30 <80 IU/l) and high (ALT ≧ 80 IU/l) ALT groups. Eleven patients were re-treated with IFN. During the follow-up period of 12 years, HCC developed in 26 patients with an average annual incidence of 3.9%. Biochemical responders to initial IFN therapy (n = 8) and those re-treated with IFN (n = 10), except 1, did not develop HCC. Cox regression analysis to evaluate risk factors for HCC occurrence, found development of Liver Cirrhosis within 3 years of initial IFN therapy(P = 0.05) and the 3 year annual average ALT post initial IFN therapy (P = 0.033) to be significant. The 12 year annual average ALT was also found to be significantly related to HCC occurrence (P = 0.016), on univariate analysis. Patients belonging to the continuously low ALT group (ALT ≦ 30 IU/l for ≧3 years), did not develop HCC or receive IFN re-treatment. In CHC patients with F3, after initial IFN therapy, keeping ALT continuously low, below 30 IU/l for 3 years or more seems important. Continuing treatment with anti-inflammatory drugs along with subsequent IFN re-treatment may prevent or delay HCC even in elderly patients

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

The targeting of the cyclin D1 oncogene by an Epstein-Barr virus promoter in transgenic mice causes dysplasia in the tongue, esophagus and forestomach

Cyclin D1 in cooperation with its major catalytic partners, cyclin-dependent kinases cdk4 and cdk6, facilitates progression through the G1 phase of the eukaryotic cell cycle, in part through phosphorylation of the retinoblastoma protein. Cyclin D1's oncogenic properties have been suggested by its cooperation with ras or adenovirus E1a to transform cultured cells, as well its overexpression in transgenic mice that leads to breast cancer. Activated by a number of different mechanisms in human cancers, the cyclin D1 gene is frequently amplified in squamous epithelial cancers derived from the head/neck and esophageal regions. In order to study the functional consequences of cyclin D1 overexpression in these squamous epithelial specific sites, we have linked the Epstein-Barr virus ED-L2 promoter to the human cyclin D1 cDNA and utilized this transgene to generate founder lines. This transgene is transcribed specifically in the tongue, esophagus and forestomach, all sharing a stratified squamous epithelium. The transgene protein product localizes to the basal and suprabasal compartments of these squamous epithelial tissues, and mice from different lines develop dysplasia, a prominent precursor to carcinoma, by 16 months of age in contrast to age-matched wild-type mice. This transgenic model is useful in demonstrating cyclin D1 may be a tumor initiating event in aero-upper digestive squamous epithelial tissues