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Tumorigenic study on hepatocytes coexpressing SV40 with Ras
Beicheng Sun1, Meizhen Chen, Christina Hawks
1Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China.
Molecular Carcinogenesis
|September 21, 2005
Summary
Human hepatocytes can become fully malignant tumors when transplanted under the kidney capsule with SV40 large T antigen (LT) and Ha-RasV12. Telomerase reverse transcriptase (hTERT) is not required for this specific neoplastic transformation.
Area of Science:
- Oncology
- Cell Biology
- Virology
Background:
- Neoplastic transformation models using SV40 large T antigen (LT), SV40 small T antigen (ST), oncogenic Ras, and human telomerase reverse transcriptase (hTERT) are established in fibroblasts.
- Previous studies have not reported on neoplastic transformation of human hepatocytes using these factors.
Purpose of the Study:
- To investigate the neoplastic transformation of human hepatocytes using a combination of SV40 LT and oncogenic Ras (Ha-RasV12).
- To evaluate the role of hTERT and protein phosphatase 2A (PP2A) inhibition in hepatocyte transformation using different transplantation models.
Main Methods:
- Utilized a cell transplantation model involving human hepatocytes (HL-7702 and HL-7703) expressing Ha-RasV12 and SV40 LT.
- Transplanted modified hepatocytes into the subrenal capsule of immunodeficient mice.
- Compared tumor development with conventional subcutaneous injections.
- Investigated the requirement of hTERT in GM-847 cells for tumorigenic growth in both subrenal capsule and subcutaneous models.
Main Results:
- Transplantation of human hepatocytes expressing Ha-RasV12 and SV40 LT into the subrenal capsule resulted in fully malignant tumors.
- Tumors failed to develop with conventional subcutaneous injections of the same cells.
- hTERT was not required for tumorigenic growth in the subrenal capsule transplantation model.
- hTERT was required for tumorigenic growth in the subcutaneous injection assay.
Conclusions:
- Human hepatocytes can undergo malignant transformation when co-expressing SV40 LT and Ha-RasV12 under the kidney capsule.
- Neither hTERT nor PP2A inhibition are necessary for malignant transformation in this subrenal capsule model.
- The requirement for hTERT in tumorigenesis differs between subrenal capsule and subcutaneous transplantation models, suggesting distinct biological mechanisms.