Immunotherapy of hepatocellular carcinoma with small double-stranded RNA

BMC Cancer

Tatyana O Kabilova¹  Larisa V Kovtonyuk¹  Evgeniy V Zonov¹  Elena I Ryabchikova¹  Nelly A Popova²  Valeriy P Nikolin²  Vasiliy I Kaledin²  Marina A Zenkova¹  Valentin V Vlassov¹  Elena L Chernolovskaya¹ 

[1] Institute of Chemical Biology and Fundamental Medicine SB RAS, 8, Lavrentiev Avenue, Novosibirsk 630090, Russia

[2] Institute of Cytology and Genetics SB RAS, 10, Lavrentiev Avenue, Novosibirsk 630090, Russia

关键词: Interferon inducer;    Hepatocellular carcinoma;    Immunostimulatory RNA;   

Others  :  858820
DOI  :  10.1186/1471-2407-14-338

 received in 2013-12-03, accepted in 2014-05-12,  发布年份 2014

【 摘 要 】

Background

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with limited therapeutic options. Since HCC has been shown to be immunogenic, immunotherapy is considered a promising therapeutic approach. Small interfering RNAs (siRNAs), depending on their structure and sequence, can trigger the innate immune system, which can potentially enhance the adaptive anticancer immune response in the tumor-bearing subjects. Immunostimulatory properties of nucleic acids can be applied to develop adjuvants for HCC treatment.

Methods

The transplantable HCC G-29 tumor in male CBA/LacSto (CBA) mice was used to study the effects of immunostimulatory RNA on tumor growth. Tumor size, metastases area in different organs of mice and mouse survival rate were analyzed. Furthermore the mouse serum IFN-α levels were measured using ELISA.

Results

In the present study, we found that a 19-bp RNA duplex (ImmunoStimulattory RNA or isRNA) with 3-nt overhangs at the 3′-ends of specific sequence displays immunostimulatory, antitumor, and antimetastatic activities in mice bearing HCC G-29. Our results demonstrate that isRNA strongly increases the level of interferon-α (IFN-α) by up to 25-fold relative to the level in mice injected with Lipofectamine alone (Mock), and to a lesser extent increases the level of proinflammatory cytokine interleukin-6 (IL-6) (by up to 5.5-fold relative to the Mock level), in mice blood serum. We showed that isRNA reliably (P < 0.05) inhibits primary tumor growth in mice compared to the mock group. Furthermore, injections of isRNA significantly enhanced necrotic processes in the center of the primary tumor, and decreased by twofold the width of the undifferentiated peripheral zone and the number of mitotic cells in this zone. The results showed that isRNA efficiently reduces the area of metastases in the liver, kidneys, and heart of CBA/LacSto mice with HCC.

Conclusions

The obtained results clearly demonstrate immunostimulatory and antimetastatic properties of the isRNAs in mice with HCC. Consequently, this short double-stranded RNA can be considered as a potential adjuvant for the therapy of HCC.

【 授权许可】

   
2014 Kabilova et al.; licensee BioMed Central Ltd.

【 图 表 】

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