Abstract
There exists an urgent medical demand at present to develop therapeutic strategies which can improve the treatment outcome of hepatocellular carcinoma (HCC). Here, we explore the biological functions and clinical significance of PBOV1 in HCC in order to push forward the diagnosis and treatment of HCC. Using theranostical nanomedicines, PBOV1 is verified to be a key oncogene which greatly promotes HCC proliferation, epithelial-to-mesenchymal transition, and stemness by activating the Wnt/β-catenin signaling pathway. Therefore, single-chain antibody for epidermal growth factor receptor (scAb-EGFR)-targeted nanomedicine effectively silencing the PBOV1 gene exhibits potent anticancer effects. In vivo HCC-targeting siRNA delivery mediated by the theranostical nanomedicine remarkably inhibits the tumor growth and metastasis. In addition, the superparamagnetic iron oxide nanocrystals (SPION)-encapsulated nanomedicines possess high MRI detection sensitivity, which endows them with the potential for MRI diagnosis of HCC. This study shows that PBOV1 represents a prognostic biomarker and therapeutic target for HCC.
Highlights
There exists an urgent medical demand at present to develop therapeutic strategies which can improve the treatment outcome of hepatocellular carcinoma (HCC)
Reverse transcriptase polymerase chain reaction (RT-PCR) and western blotting analyses showed that Prostate and breast cancer overexpressed 1 (PBOV1) mRNA and protein levels were markedly upregulated in multiple HCC cell lines including Hep3B, BEL7402, SNU423, SMMC-7721, PLC/PRF/5, Huh[7], HLE, HLF, HepG2.2.1, SK-Hep[1], and HepG2, as compared with human normal hepatocyte cell lines (L02 and HHL-5) (Fig. 1e, Supplementary Fig. 1b)
As shown in the western blotting assay (Fig. 6c), the upregulated angiogenesis marker (HIF-1α) and mesenchymal markers (N-cadherin and Vimentin), but downregulated epithelial markers (α-Catenin and E-cadherin), were detected in the TO group, whereas the TS1 and TS2 groups behaved the other way around. These results demonstrated that PBOV1 promoted the metastasis of HCC in vivo through inducing the epithelial-to-mesenchymal transition (EMT) process, which was in line with the in vitro results on migration and invasion of HCC (Fig. 3e–g)
Summary
There exists an urgent medical demand at present to develop therapeutic strategies which can improve the treatment outcome of hepatocellular carcinoma (HCC). Samusik et al.[7] demonstrated the high levels of PBOV1 expression in breast cancer These studies provide preliminary in vitro results that PBOV1 overexpression promoted cancer cell proliferation, its effect on EMT and CSCs regulation has not been reported. Surface attachment of specific ligands recognizing molecular biomarkers on cancer cytomembrane (e.g., folate[12] and antibodies13) may improve tumor-targeted drug delivery of nanomedicines both in vitro and in vivo[14]. A HCC-targeting and MRI-visible nonviral carrier, EGFR single-chain antibody-modified graft copolymer of polyethylene glycol (PEG) and polyethylenimine (PEI) complexing SPION (abbreviated as scAb-EGFR-PEG-g-PEISPION), was developed to mediate effective nucleic acid delivery to HCC both in vitro and in vivo. The potential of theranostical nanomedicine for treatment of HCC was explored
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