Oestrogen attenuates tumour progression in hepatocellular carcinoma

• Published in: The Journal of pathology 2012-10, Vol.228 (2), p.216-229
• Main Authors: Xu, Hanwen, Wei, Yinna, Zhang, Yu, Xu, Yichen, Li, Feng, Liu, Jing, Zhang, Wei, Han, Xiaodong, Tan, Renxiang, Shen, Pingping
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Hormonal - metabolism; Antineoplastic Agents, Hormonal - pharmacology; Apoptosis - drug effects; Biological and medical sciences; Biomarkers, Tumor - metabolism; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Castration; Cell Cycle - drug effects; Cell Line, Tumor; Disease Progression; Drug Screening Assays, Antitumor; Estrogens - deficiency; Estrogens - metabolism; Estrogens - pharmacology; Female; Gastroenterology. Liver. Pancreas. Abdomen; gender disparity; hepatocellular carcinoma; Investigative techniques, diagnostic techniques (general aspects); Liver Neoplasms - drug therapy; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Longevity; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Neoplasm Invasiveness - prevention & control; Neoplasm Transplantation; NF-kappa B - metabolism; oestrogen; orthotopic tumour model; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Protein Binding - drug effects; Sex Factors; Transplantation, Homologous; Tumors; tumour progression
• ISSN: 0022-3417; 1096-9896
• DOI: 10.1002/path.4009

The precise mechanisms underlying gender disparity in hepatocellular carcinoma (HCC) progression and prognosis are not understood. We demonstrate that oestrogen attenuates HCC progression in vitro and in vivo, and this may contribute to the gender differences in HCC behaviour. To investigate the role of oestrogen in HCC progression, we developed an orthotopic homograft tumour model by liver implantation of H22 cells. In combination with male castration, female ovariectomy, and oestrogen treatment, we tested the hypothesis that oestrogen contributes to gender disparity in this model. Pathological analyses were performed to examine the changes in biological behaviour of liver cancer cells, and two cell lines were used to investigate possible molecular mechanisms of the suppressive effect of oestrogen. Our data showed that oestrogen modulates HCC malignancy in vivo by reducing tumour cell invasion, arresting cell cycle progression, and promoting apoptosis, characterized by decreased expression of MMP‐2, MMP‐9, PCNA, cyclin A, cyclin D1, and Bcl‐2, and increased expression in cleaved caspase 3. Through in vitro assays, we further confirmed the changes in expression levels of these related proteins, gained insights into the molecular cascades of oestrogen‐induced HCC suppression, and indicated the oestrogen receptor α‐mediated inhibition of NF‐κB binding activity as a pivotal event in this process. This study represents a novel description of the mechanisms regarding the suppressive effects of oestrogen on HCC, adding a new understanding to the gender disparity in HCC progression. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.