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

Abstract

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 b-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/ b-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 potential for combined gene therapy and MRI diagnosis of HCC. (HEPATOLOGY 2016;63:1240-1255 H epatocellular carcinoma (HCC) is one of the most frequently diagnosed and aggressive malignancies, and more efficient therapeutic interventions are necessary for HCC.(1) Approximately 630,000 new cases of HCC are reported throughout the world every year, and approximately 55% of these cases occur in China. Despite the discovery of the molecular mechanisms of hepatocarcinogenesis and multimodal treatments involving extensive surgical resection, liver transplantation, radiotherapy, chemotherapy, and immunotherapy, the 5-year relative survival rates of patients with HCC are generally less than Abbreviations: ALT, alanine transaminase; HCC, hepatocellular carcinoma; IHC, immunohistochemical; MRI, magnetic resonance imaging; NIRF, near infrared fluorescence imaging; PEG, polyethylene glycol; PEI, polyethylenimine; RNAi, RNA interference; siRNA, small interfering RNA; SPION, superparamagnetic iron oxide nanoparticles; TBIL, total bilirubin; TBLR1, transducin b-like protein 1-related protein; TUNEL, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling; VEGF, vascular endothelial growth factor.

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…Multifunctional delivery systems that carry therapeutic and diagnostic imaging agents with FA are emerging concept for effective targeted therapy. The diagnostic imaging agents contain fluorophores, quantum dots (QDs), 110 small-molecule paramagnetic agents, 111,112 SPIO, [113][114][115][116][117] and so forth. Wang et al 110 designed a smart multifunctional polymeric micelle for targeted therapy of HCC.…”

Over-Expression of TBL1XR1 Indicates Poor Prognosis of Serous Epithelial Ovarian Cancer

“…TBL1XR1 siRNA#1: 5′-TCT CTA GAT TGG AAT AGT GAAdTdT-3′ (Guo et al 2016) TBL1XR1 siRNA#2: 5′-CGT AAT GCC TGA TGT AGT AdTdT-3′ Negative control siRNA (ncRNA): 5′-TTC TCC GAA CGT GTC ACG TdTdT-3′…”

Role of cytochrome P450 2J2 on cell proliferation and resistance to an anticancer agent in hepatocellular carcinoma HepG2 cells

“…Robust cell proliferative capacity and resistance to anticancer agents are major hurdles to the development of efficient chemotherapy, and abnormal cell proliferation and apoptotic cell death have been extensively studied to identify potential therapeutic targets against human cancer (30). Various cellular components, including hypoxia-inducible factor-1α (31), transducin β-like protein 1-related protein (32) and fibroblast growth factor receptor 4 (33), have been shown to contribute to cancer cell proliferation, and due to their anti-apoptotic properties, they have been studied as putative targets for cancer therapy (31)(32)(33). The results of the present study revealed that CYP2J2 also serves important roles in inducing cell proliferation and inhibiting the cell death induced by anticancer agents.…”