Promising therapeutic efficacy of a novel reduced expression in immortalized cells/dickkopf-3 expressing adenoviral vector for hepatocellular carcinoma.

Abstract

BACKGROUND AND AIM:

Reduced expression in immortalized cells (REIC)/dickkopf-3 (Dkk-3) is a tumor suppressor gene that is downregulated in various cancers. In our previous study of prostate cancer, the REIC/Dkk-3-expressing adenoviral vector (Ad-REIC) was found to induce cancer-selective apoptosis. This study recently developed a novel super gene expression (SGE) system and used this system to re-construct an Ad-REIC vector, termed the Ad-SGE-REIC, to achieve more effective therapeutic outcomes. In this study, the therapeutic effects of Ad-SGE-REIC on hepatocellular carcinoma (HCC) was assessed.

METHODS:

Human HCC cell lines (HLE, Huh7, HepG2, HLF, SK-Hep1, and PLC), human HCC tissues, and mouse HCC cell line (Hepa1-6) were used in this study. REIC/Dkk-3 expression was assessed by immunoblotting and immunohistochemistry. The relative cell viability and the apoptotic effect were examined in vitro, and the anti-tumor effects of Ad-SGE-REIC treatment were analyzed in the mouse xenograft model. This study additionally assessed anti-tumor immunological effects on the immunocompetent mice.

RESULTS:

REIC/Dkk-3 expression was decreased in HCC cell lines and HCC tissues. Ad-SGE-REIC reduced cell viability and induced apoptosis in HCC cell lines (HLE and Huh7), inhibited tumor growth in the mouse xenograft model, and demonstrated in vivo anti-cancer immunostimulatory effects on the HCC cell line (Hepa1-6).

CONCLUSIONS:

Ad-SGE-REIC treatment not only enhanced cell killing effects in vitro but also elicited significant therapeutic effects, with tumor growth suppression, in vivo. REIC/Dkk-3 gene therapy using Ad-SGE-REIC potentially represents an innovative new therapeutic tool for HCC.

• Authors: Hiroaki Sawahara, Hidenori Shiraha, Daisuke Uchida, Hironari Kato, Ryo Kato, Atsushi Oyama, Teruya Nagahara, Masaya Iwamuro, Shigeru Horiguchi, Koichiro Tsutsumi, Mari Mandai, Tetsushige Mimura, Nozomu Wada, Yasuto Takeuchi, Kenji Kuwaki, Hideki Onishi, Shinichiro Nakamura, Masami Watanabe, Masakiyo Sakaguchi, Akinobu Takaki, Kazuhiro Nouso, Takahito Yagi, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Okada
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 32 Issue 10 Pg. 1769-1777 (Oct 2017) ISSN: 1440-1746 [Electronic] Australia
• PMID: 28168749 (Publication Type: Journal Article)
• Copyright: © 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

Chemical References

• Adaptor Proteins, Signal Transducing
• Chemokines
• DKK3 protein, human
• Intercellular Signaling Peptides and Proteins

Topics

• Adaptor Proteins, Signal Transducing
• Adenoviridae (genetics)
• Animals
• Apoptosis (genetics)
• Carcinoma, Hepatocellular (pathology, therapy)
• Cell Line, Tumor
• Chemokines
• Disease Models, Animal
• Gene Expression
• Genes, Tumor Suppressor
• Genetic Therapy (methods)
• Genetic Vectors (genetics, therapeutic use)
• Hep G2 Cells
• Humans
• Intercellular Signaling Peptides and Proteins (genetics, metabolism, therapeutic use)
• Liver Neoplasms (pathology, therapy)
• Mice, Inbred BALB C
• Neoplasm Transplantation