Recombinant adeno-associated virus expressing a p53-derived apoptotic peptide (37AA) inhibits HCC cells growth in vitro and in vivo.

Hongyong Zhang,Qingguang Liu,Yanxia Bai,Yufeng Wang,Yuan Shao,Zhenhua Ma,Shengli Wu,Jigang Bai

doi:10.18632/oncotarget.15160

Hongyong Zhang, Qingguang Liu + Show 6 more

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https://doi.org/10.18632/oncotarget.15160

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Abstract

Recent studies have confirmed that a p53-derived apoptotic peptide (37AA) could act as a tumor suppressor inducing apoptosis in multiple tumor cells through derepressing p73. However, the tumor suppressive effects of recombinant adeno-associated virus (rAAV) expressing 37AA on HCC cells are still unknown. In this study, we successfully constructed a recombinant rAAV expressing 37AA. In vitro and in vivo assays showed that transfection of NT4-37AA/rAAV in HCC cells strongly suppressed cell proliferation, induced apoptosis, and up-regulated the cellular expression of p73. NT4-37AA/rAAV transfection markedly slowed Huh-7 xenografted tumor growth in murine. Pretreatment of HCC cells with p73 siRNA abrogated these effects of NT4-37AA/rAAV. Furthermore, we found that expression of p73 was upregulated and the formation of P73/iASSP complex was prevented when 37AA was introduced into HCC cells. Taken together, these results indicate that introduction of 37AA into HCC cells with a rAAV vector may lead to the development of broadly applicable agents for the treatment of HCC, and the mechanism may, at least in part, be associated with the upregulation of p73 expression and reduced level of P73/iASSP complex.

Highlights

Hepatocellular carcinoma (HCC) is one of the most deadly cancers in humans [1]
We found that expression of p73 was upregulated and the formation of P73/iASSP complex was prevented when 37AA was introduced into HCC cells
These results indicate that introduction of 37AA into HCC cells with a recombinant adenoassociated virus (rAAV) vector may lead to the development of broadly applicable agents for the treatment of HCC, and the mechanism may, at least in part, be associated with the upregulation of p73 expression and reduced level of P73/iASSP complex

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most deadly cancers in humans [1]. Despite considerable therapeutic progress, patients with HCC still face a high incidence of postoperative recurrence and metastases, even when treatments have been considered potentially curative [2]. Its clinical benefits remain modest with an average overall survival of only 10.7 months for advanced HCC patients [3]. Recent advances in the molecular pathogenesis of HCC revealed that complex genetic and epigenetic alterations, chromosomal aberrations, mutations, and altered molecular pathways lead to the development of HCC [4, 5]. Analyses of these aberrant alterations involved in the development of HCC could help us to identify potential diagnostic markers and new molecular targets of HCC. Various targeted therapies are currently being explored for combating HCC, and accumulating evidence suggests that combination therapy targeting different pathways, such as angiogenesis, signal transduction and epigenetic dysregulation of tumors, will potentiate antiHCC effects and provide perspectives on future clinical trials in HCC [6, 7]

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