Anti-angiogenic efficacy of 5'-triphosphate siRNA combining VEGF silencing and RIG-I activation in NSCLCs

Dongmei Yuan; Mao Xia; Gang Meng; Chun Xu; Yong Song; Jiwu Wei

doi:10.18632/oncotarget.4869

Anti-angiogenic efficacy of 5'-triphosphate siRNA combining VEGF silencing and RIG-I activation in NSCLCs

Oncotarget. 2015 Oct 6;6(30):29664-74. doi: 10.18632/oncotarget.4869.

Authors

Dongmei Yuan^{1

2}, Mao Xia^{1

3}, Gang Meng¹, Chun Xu¹, Yong Song², Jiwu Wei^{1

4}

Affiliations

¹ Jiangsu Key Laboratory of Molecular Medicine, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.
² Department of Respiratory Medicine, Jinling Hospital, Nanjing, China.
³ Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
⁴ Nanjing University Hightech Institute at Suzhou, Suzhou, China.

Abstract

Short interfering RNA (siRNA) targeting angiogenic factors and further inhibiting tumor angiogenesis, is one of the potent antitumor candidates for lung cancer treatment. However, this strategy must be combined with other therapeutics like chemotherapy. In this study, we designed a 5'-triphosphate siRNA targeting VEGF (ppp-VEGF), and showed that ppp-VEGF exerted three distinct antitumor effects: i) inhibition of tumor angiogenesis by silencing VEGF, ii) induction of innate immune responses by activating RIG-I signaling pathway, and thus activate antitumor immunity, iii) induction of apoptosis. In a subcutaneous model of murine lung cancer, ppp-VEGF displayed a potent antitumor effect. Our results provide a multifunctional antitumor molecule that may overcome the shortages of traditional antiangiogenic agents.

Keywords: NSCLC; RIG-I; VEGF; anti-angiogenesis; short interfering RNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / genetics
Blotting, Western
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / therapy
Cell Line, Tumor
DEAD Box Protein 58
DEAD-box RNA Helicases / genetics*
DEAD-box RNA Helicases / metabolism
Humans
Immunohistochemistry
Interferon Type I / metabolism
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Lung Neoplasms / therapy
Male
Mice, Inbred C57BL
Neovascularization, Pathologic / genetics*
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / therapy
Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
Polyphosphates / metabolism
RNA Interference
RNA, Small Interfering / genetics*
RNA, Small Interfering / metabolism
RNAi Therapeutics / methods
Receptors, Immunologic
Reverse Transcriptase Polymerase Chain Reaction
Tumor Burden / genetics
Vascular Endothelial Growth Factor A / genetics*
Vascular Endothelial Growth Factor A / metabolism

Substances

Interferon Type I
Platelet Endothelial Cell Adhesion Molecule-1
Polyphosphates
RNA, Small Interfering
Receptors, Immunologic
Vascular Endothelial Growth Factor A
RIGI protein, human
DEAD Box Protein 58
DEAD-box RNA Helicases
triphosphoric acid