Theranostical nanosystem-mediated identification of an oncogene and highly effective therapy in hepatocellular carcinoma.

Abstract

UNLABELLED:

Because the primary surgical treatment options for hepatocellular carcinoma (HCC)-including hepatic resection and liver transplantation-often fail due to recurrence and metastasis, identifying early prognostic biomarkers and therapeutic targets for HCC is of great importance. This study shows that transducin β-like protein 1-related protein (TBLR1) is a key HCC oncogene that plays important roles in HCC proliferation, antiapoptosis, and angiogenesis by regulating the Wnt/β-catenin pathway. The folate-targeted theranostic small interfering RNA (siRNA) nanomedicine Fa-PEG-g-PEI-SPION/psiRNA-TBLR1 effectively silences the TBLR1 gene in different human HCC cell lines in vitro and in human HCC samples in vivo, resulting in the simultaneous suppression of HCC cell proliferation, antiapoptosis, and angiogenesis. Because of its multi-anticancer functions against HCC, intravenous injection of the folate-targeted siRNA nanomedicine into nude mice bearing intrahepatic or subcutaneous xenografts of human HCC has a significant therapeutic effect. Tumor growth in those animals was almost completely inhibited by treatment with Fa-PEG-g-PEI-SPION/psiRNA-TBLR1. Moreover, the SPION-encapsulated polyplexes possess high magnetic resonance imaging (MRI) detection sensitivity, which makes tumor-targeted siRNA delivery easily trackable using the clinical MRI technique.

CONCLUSION:

The theranostic siRNA nanomedicine examined here possesses great theranostic potential for combined gene therapy and MRI diagnosis of HCC.

• Authors: Yu Guo, Jing Wang, Lu Zhang, Shunli Shen, Ruomi Guo, Yang Yang, Wenjie Chen, Yiru Wang, Guihua Chen, Xintao Shuai
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 63 Issue 4 Pg. 1240-55 (Apr 2016) ISSN: 1527-3350 [Electronic] United States
• PMID: 26680504 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Association for the Study of Liver Diseases.

Chemical References

• Nuclear Proteins
• RNA, Small Interfering
• Receptors, Cytoplasmic and Nuclear
• Repressor Proteins
• TBL1XR1 protein, human

Topics

• Aged
• Analysis of Variance
• Animals
• Apoptosis (genetics)
• Carcinoma, Hepatocellular (genetics, mortality, therapy)
• Disease Models, Animal
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Therapy (methods)
• Heterografts
• Humans
• Kaplan-Meier Estimate
• Liver Neoplasms (genetics, mortality, therapy)
• Magnetic Resonance Imaging (methods)
• Male
• Mice
• Mice, Nude
• Middle Aged
• Molecular Targeted Therapy (methods)
• Multivariate Analysis
• Nuclear Proteins (genetics)
• Oncogenes
• Proportional Hazards Models
• RNA, Small Interfering (administration & dosage)
• Random Allocation
• Receptors, Cytoplasmic and Nuclear (genetics)
• Repressor Proteins (genetics)
• Treatment Outcome
• Tumor Cells, Cultured
• Wnt Signaling Pathway (genetics)