HER2-siRNA delivered by EGFR-specific single chain antibody inhibits NSCLC cell proliferation and tumor growth

Yuan Lu; Yuan Wang; Mi Zhang; Li Liu; Fakai Li; Jian Zhang; Mingxiang Ye; Hu Zhao; Jing Zhao; Bo Yan; Angang Yang; Rui Zhang; Xia Li; Xinling Ren

doi:10.18632/oncotarget.8053

HER2-siRNA delivered by EGFR-specific single chain antibody inhibits NSCLC cell proliferation and tumor growth

Oncotarget. 2016 Apr 26;7(17):23594-607. doi: 10.18632/oncotarget.8053.

Authors

Yuan Lu¹, Yuan Wang¹, Mi Zhang², Li Liu^{1

3}, Fakai Li¹, Jian Zhang¹, Mingxiang Ye¹, Hu Zhao⁴, Jing Zhao⁵, Bo Yan⁵, Angang Yang⁶, Rui Zhang⁵, Xia Li⁵, Xinling Ren¹

Affiliations

¹ Department of Respiratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
² Department of Respiratory Medicine, PLA General Hospital, Beijing, China.
³ Department of Geriatrics, Xianyang Central Hospital, Xianyang, China.
⁴ Organ Transplant Institute, Fuzhou General Hospital (DongFang Hospital), Xiamen University, Fuzhou, China.
⁵ State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, China.
⁶ State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China.

Abstract

Overexpression of human epidermal growth factor receptor type2 (HER2) is closely associated with aggressive progression and poor prognosis in non-small cell lung cancer (NSCLC). Here, we generated an EGFR-scFv-arginine nonamer peptide fusion protein (scFv-9R) as a cargo to deliver HER2 specific siRNA into HER2-positive NSCLC cells both in vitro and in vivo. HER2-siRNAs delivered by scFv-9R effeciently silenced HER2 expression in EGFR-positive NSCLC cells, and consequently resulted in G1 arrest and cell growth inhibition. Importantly, intravenous injection of scFv-9R/HER2-siRNA complex markedly suppressed growth of EGFR-positive NSCLC xenograft in nude mice, resulting from downregulated HER2 expression, reduced cell proliferation and enhanced cell apoptosis. Collectively, our study provides a novel therapeutic strategy for the treatment of EGFR-positive, HER2-overexpressed NSCLC.

Keywords: EGFR; HER2; non-small cell lung cancer; single-chain viable-fragment antibody; small interfering RNA.

MeSH terms

Adenocarcinoma / genetics
Adenocarcinoma / prevention & control
Adenocarcinoma / secondary
Animals
Apoptosis
Biomarkers, Tumor
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / prevention & control
Carcinoma, Non-Small-Cell Lung / secondary
Carcinoma, Squamous Cell / genetics
Carcinoma, Squamous Cell / prevention & control
Carcinoma, Squamous Cell / secondary
Cell Cycle
Cell Proliferation*
ErbB Receptors / immunology*
Female
Follow-Up Studies
Humans
Lung Neoplasms / genetics
Lung Neoplasms / pathology
Lung Neoplasms / prevention & control*
Lymphatic Metastasis
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Neoplasm Invasiveness
Prognosis
RNA, Small Interfering / administration & dosage
RNA, Small Interfering / genetics*
Receptor, ErbB-2 / antagonists & inhibitors*
Receptor, ErbB-2 / genetics
Single-Chain Antibodies / pharmacology*
Survival Rate
Tumor Cells, Cultured
Xenograft Model Antitumor Assays

Substances

Biomarkers, Tumor
RNA, Small Interfering
Single-Chain Antibodies
EGFR protein, human
ERBB2 protein, human
ErbB Receptors
Receptor, ErbB-2