siRNA-mediated Erc gene silencing suppresses tumor growth in Tsc2 mutant renal carcinoma model.
Silencing of gene expression by small interfering RNAs (siRNAs) is rapidly becoming a powerful tool for genetic analysis and represents a potential strategy for therapeutic product development. However, there are no reports of systemic delivery of siRNAs for stable treatment except short hairpin RNAs (shRNAs). On the other hand, there are many reports of systemic delivery of siRNAs for transient treatment using liposome carriers and others. With regard to shRNAs, a report showed fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Therefore, we decided to use original siRNA microspheres instead of shRNA for stable treatment of disease. In this study, we designed rat-specific siRNA sequences for Erc/mesothelin, which is a tumor-specific gene expressed in the Eker (Tsc2 mutant) rat model of hereditary renal cancer and confirmed the efficacy of gene silencing in vitro. Then, by using siRNA microspheres, we found that the suppression of Erc/mesothelin caused growth inhibition of Tsc2 mutant renal carcinoma cells in tumor implantation experiments in mice.
Imamura
Osamu
O
Department of Pathology and Oncology, Juntendo University School of Medicine, Tokyo, Japan.
Okada
Hiroaki
H
Takashima
Yuuki
Y
Zhang
Danqing
D
Kobayashi
Toshiyuki
T
Hino
Okio
O
D000818:Animals; D018394:CA-125 Antigen / Q000502:physiology; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins; D020868:Gene Silencing; D007680:Kidney Neoplasms / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000090204:Mesothelin; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D034741:RNA, Small Interfering / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018394:CA-125 Antigen; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; C000715528:Msln protein, mouse; C000715529:Msln protein, rat; D034741:RNA, Small Interfering; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000090204:Mesothelin